Plague Inc. Smallpox Scenario Mega-Brutal(3 Biohazard) Guide & Walkthrough

The Smallpox scenario is one of the several scenarios in Plague inc. where you're given a chance to spread an old plague that has decimated a large number of the human population. You are given a specific set of symptoms, transmissions and abilities you'll have to take advantage of to spread the plague and kill with it.

Completing this scenario in mega-difficulty while aiming for 3 biohazards, at the same time, will be extremely hard. Why? Because if you haven't tried this scenario yet, the cure progression fills up at an extremely fast rate. You'll definitely scratch your head at how fast the cure gets completed in this scenario.

Not only will you have to battle the super quick progression of the cure, you'll also have to evolve vaccine shields to stop the decrease of your infected humans.
Let me explain this a bit more. Right at the beginning of the game, countries will fight your smallpox infection with vaccines they already have in hand. These vaccines will continually lessen your infection count until you do something about it. The first Vaccine shield will only help you long enough to fully infect your origin country.

After a while, countries will then start to experiment on vaccines. These vaccines are EJ2, EJ7, and EJ13. Again, these vaccines will slow down and decrease your infection count significantly. Each country will release one of these three vaccines at random. You can always check your news headlines to check which one a country just released and evolve the corresponding vaccine shield to nullify their vaccines. In my opinion, evolving all three of these vaccine shield is really not a good idea. Not only will it take a considerable amount of DNA, it will also hinder you from evolving much needed abilities that slow down the cure. Evolving EJ2 and EJ7 should be enough to battle the vaccines the world keeps throwing at you.

You'll also be starting with a fixed set of evolved symptoms. As you may notice, you start with a plague that's quite lethal and severe. You can devolve a lethal symptom, if you want, but I am completely against that since it costs DNA. If you choose to work with these set of symptoms though, be prepared to be spotted early and even be placed on the WHO watch list at an early stage.

Before I start with the guides and strategies, there's a few things that I'd like everyone to know, just to clear up some questions that might appear with these guides.

A few things to remember:

  • The guides that are about to be posted, in regards with this scenario, were made through countless games and errors. Therefore,
  • We can't always account for the random events and infection order of every game. 
  • Every game is different, always be prepared to the strategy, as you see fit.
  • In order to get a 3 biohazard score, you will need to finish within 307 days(not entirely sure of this), cure completion does not matter.(It does)
  • If at first you don't succeed, try again.
Now, the guides:

Strategy 1: Submitted Strategy

Spicy's comments: Strategy 2 is currently based on this one, but with a few changes. This specific strategy has worked for me once then refused to work with me again.

This strategy has been submitted by an anonymous user that has commented in one of our posts. It's a YouTube video of a Plague Inc. Evolved game on the Smallpox scenario. Several users have already expressed that this has worked for them in the mobile version of the game so I decided to include this along with the guide.
 This video has been uploaded by: Pan S Clock on Youtube

Here's his detailed explanation on this strategy.
Section 1 : Genetic Code
a) Metabolic Jump
I choose this, as I think, due to the fast process of spreading the disease, ATP Boost would not be the best for a generally fast game as its effects soon will be outweighted by the possible gain of MJ. Catalytic Switch and Cytochrome Surge are also not the best choice, because it is all about a fast midgame. Metabolic Jump, in my opinion, has got the best effect on this part of the game, because the speed of infecting new countries directly correlates to the speeding-up-effect of MJ.
b) Darwinist
It is more likely, that a mutation will do good than harm to your game, as stealth-mode is no option. You can in fact get an enormous boost through the right ones. So Creationist is not a good choice in this case. Genetic Mimic is not needed and the cure is so fast, it won’t help as much as a nice additional symptom does. The same goes for the other two, they make the cure faster and transmissions or abilities do less likely give you that edge a symptom can do.
c) Aquacyte
If everything works perfect, there are still the islands and some of them don’ t have an airport. So be an aquacyte for perfect chances of reaching them fast enough.
d) Ruhrophile
Get’ s you going in most continents and gives you a boost in your startingcountry, which is India, if you’ ll try my strategy.
e) Trans-Stasis
You have to get the transmissions quick and cheap. They speed everything up - infections and rate of mutation.

Section 2: Where to start
I choose India, as it has both, airport and seaport, has a hot and humid climate, is rural and having it infected completely gives you much DNA, sometimes only during the process, sometimes mainly when it’s done. And even better, China behaves as a DNA-donor, too! It’s close by and you always have a foothold into it, before India is finished.

Section 3: Here we go
Fomites 1 (7)
Water 1 (8)
Waiting for decrease in people infected. They die but infection seems to have stopped, so:
Vaccine Shield (10) à infection kicks in again, 2 DNA left..nice:
Abscesses (2)
Air 1 (8) or Water 2 (15) or Droplets 2 (4)? let’ s see how fast we get DNA. Orange DNA: 3 in stack, not enough even for Droplets 2. Red DNA: 6 in stack. Well, droplets? No, wait a second and look if ships or/and planes are starting early. Oh, nice, transmission by land: 10 in stack. Air 1? Yes, we have already infected over 1000 000, which is when transmission by plane usually starts in India.
Air 1 (8)
Ok. Did not take long till 12 DNA are in stack. Go for Water 2 (15) or Air 2 (14). Red DNA: 16 in stack. Air 2 (14) or Water 2 (15)? Water 2! Helps in India and for getting the islands.
Water 2 (15)
Orange DNA without waiting long for it: 5 in stack. Go for droplets 2 (4) boosting transmission by plane even more.
Droplets 2 (4)
Red DNA, nearly immediately: 5 in stack. I’ll have droplets 3 (5) please. Now the planes should really get going.
Droplets 3 (5)
Orange DNA, 2 red ones, one by plane, one by ship short after another: 15 in stack.
Air 2 (14)
Short waiting: 9 in stack.
Fomites 2 (8) aiming for maxing out transmission by ship and plane. Need 15 now for Extreme Bioaerosol (15). India fully infected: + 30 DNA: 37 in stack.
Extreme Bioaerosol (15)
Insect 1 (8)
Waiting for some DNA, need 19, for Insect 2, which is possible without waiting too long, as we’ve still 14 DNA left. Otherwise I would prefer getting Blood 1 or Livestock 1 and skip over getting some abilities for reaching new horizons.
Insect 2 (19)
MUTATION 1: Acute Encephalitis. Nice one. Making your disease a slice more deadly in the beginning without generating overwhelming fear gives your game a big bonus.
Cold Resistance 1 (8)
Drug Resistance 1 (13)
Cold Resistance 2 (15) now wealthy and cold countries don’t block you. For the wealthy ones, of course, we need to speed up, but let’s take what we get till then. EJ2 - Vaccine is a point to think about now. Let’s see how DNA comes in. 29 for the Drug Resistance, 19 for countering EJ2. One more for the leftover due to non-static abilities. Many new countries in a short time!
Drug Resistance 2 (29)
And directly enough other countries. Here we go now!
EJ2 Vaccine Shield (20)
From now on, we can switch back to transmissions and, if intended, to symptoms, too. Placed on Watchlist. Cure will speed up now.
Livestock 1 (7)
Livestock 2 (12), still 5 left, so let’s get vomiting (4) heading towards diarrhea (8), which gives a good boost in infectivity and makes dysentery a quick choice for us later.
Vomiting (4)
Blood 1 (8)
Diarrhea (8)
We are doing well! So why not have some insurance and get Genetic Hardening 1 (13)? By the way, China takes up pace now.
Genetic Hardening 1 (13)
Oh, 9 left, let’s use 8 and get Corneal Ulceration (8), which also slows the cure.
Corneal Ulceration (8)
Cure 31 %? I don’t like it!
Genetic Hardening 2 (30)
Things will get more expensive now, we’ve got many infected! Think this will change soon! Damn, they must be concerned about us lovely small pox. Soon they will throw the EJ7 after us. Have that shield now!
EJ7 Vaccine Shield (30)
MUTATION 2: Dysentery. Not too heavy a fear for them as it seems. Most time they will not close boarders because of that, or let’s say not quickly enough. So keep it. It’s worth the risk for its boost to infection rates and in lethality. There is also just Greenland left, which can stop us from getting them all. Cure: 34 days left. Thanks China. Great boost! Now 91 in stack.
Blood 2 (15)
Now we save some DNA for the final strike and the case that we have to or want to counter the cure.
Extreme Hematophagy (24)
They focus on us now, so show them the shuffle.
Genetic Reshuffle 1 (28) Costs are decreasing now, due to the large amount of people already dead.
MUTATION 3: Coma. What a luck! Perfectly timed. Thanks.
Greenland got infected. Let’s monitor how infection progresses and add something nice.
Necrosis (24)
Pulmonary Oedema (13)
Immune Suppression (14)
Genetic Reshuffle 2 (33)
Cure: 63 days left, 92 % dead, no healthy country. Sit back, relax, get some more symptoms and the next reshuffle.
Osteomyelitis (12)
MUTATION 4: Hyper Sensitivity
Symptom Combo: Projectile Vomiting
Genetic Reshuffle 3 (36)
MUTATION 5: Inflammation
Victory: 292 days

Strategy 2: Spicy's strategy

Current success rate:

for the last five games with this strategy, I've won 2 out of 5 games. Here's a short explanation of how, I believe, I won or lost on games.
  1. Win - Necrosis evolved early
  2. Win - Coma evolved early
  3. Lost - Placed on WHO watch list too early, this events further boosts the already unfair cure progression rate
  4. Lost - Infected people in Greenland died to fast. Necrosis wasn't able to infect new people.
  5. Lost - Placed on WHO watch list even before the second evolution. This happens some times.

Recommendations, Tips, and Comments

  1. If you are placed on the WHO watch list at a very early stage(India not fully infected, for example), just restart the game. When this happens, the cure progress gets significantly boosted and without the proper cure slowing abilities and symptoms, the cure will be finished within a few months.
  2. Random symptom mutations play a big role in this strategy, they could either make or break your game.
  3. Be prepared to change strategies mid-way, if you think it's necessary.
  4. I don't think the cure completion affects the success of getting a 3 biohazard score.
  5. I had a game where I finished within 305 days with 99% Cure completion and still got a 3 Biohazard score.
  6. I somewhat recommend to play with this strategy in normal speed.
  7. Further tips and recommendations will be added upon further testing.

Recommended Gene Setup:

  • ATP Boost
  • Aquacyte
  • Trans-Stasis
  • Darwinist
  • Hydrophile

The Guide:

1.) Before selecting a country to start in, evolve Insect 1
2.) Start your plague in India
3.) Evolve the following in this order:
  • Fomites 1 - High probability of getting spotted right after evolving this.
  • Vaccine Shield - the number of infected people might decrease before getting this. Don't worry
  • Water 1
  • Air 1
  • Water 2
  • Droplets 2 & 3
  • Air 2
  • Fomites 2
  • Extreme Bioaerosol
  • Insect 2
  • Cold Resistance 1
  • Drug Resistance 1
  • Cold Resistance 2
  • Drug Resistance 2
  • EJ2 Vaccine Shield - you might want to change this if a different vaccine gets released, but I really recommend getting this one.
  • Livestock 1 & 2
  • Genetic Hardening 1
  • Corneal Ulceration - Skip this if it has already mutated.
  • Genetic Hardening 2
  • EJ7 Vaccine Shield - I recommend only getting EJ2 and EJ7 as vaccine shields. Getting the third one will prove to be costly and better allocated to slow down the cure
  • Blood 1 & 2
  • Extreme Hematophagy
  • Genetic Re-Shuffle
  • Necrosis - Skip if already mutated, you really want this symptom to mutate early to increase success rate
  • Coma - Again, skip if already mutated.
  • Genetic Re-Shuffle 2
  • Genetic Re-Shuffle 3
4.) At this point, it's up to you to evolve symptoms or abilities as you see fit. Every cure slowing symptom and ability, and also every transmission, has been evolved at this point, so I recommend getting either lethal symptoms(if everyone's already infected) or infectious symptoms(If some people are yet to be infected).

I hope these strategies have helped you get those 3 biohazards in smallpox Mega-Brutal. If you have any other helpful tips or strategies, please comment them below to help us improve these guides. HSG!


  1. I have not beat smallpox yet (however I have not tried these strategies) but it is extremely important that if a popup appears that says that your disease was place on WHO watchlist or a (your disease name here) awareness day. This will increase cure efforts by A LOT and the disease will be easily cured

  2. Replies
    1. Not neccessarily, it also depends on your cure percentage, you probably got around 95%. I got 66514 in 315 days 86%.
      "In order to get a 3 biohazard score, you will need to finish within 307 days(not entirely sure of this), cure completion does not matter."
      This is not true, cure perecentage also matters (however it is not nearly as much in the regular game). You will probably need 307 days with a 95%-100% cure

      On a slightly unrelated subject, smallpox and other virus scenarios seem to count for speed runs.

    2. Thank you for clearing this up, Iamteehee. Going to make changes to the guide.

  3. Thanks for menioning my guide:)



  4. aghhh
    i was really close (like only 50000 people left) and then the cure completed!

    1. Yep me too, goddamn Greenland lol.

  5. Can confirm that early mutated Necrosis helps massively. Got really lucky and then also got Coma via mutation. Finished in 283 days with Greenland (obviously) being the last country to become fully infected. Finally got my 3 hazards, #ALLHAILSPICY

  6. I finally buried the planet with smallpox and the results were EEEEEEEEPIIIIIIIC!!! 77% cure completion, human race eradicated in 165 days, score 130309!!!! I swear! I have a screenshot for proof, I just don't know how to post or show it. The only thing is its a combination of both strategies and random events and I'm not sure how to duplicate it and if I did, I don't know if if share it. It's just the truth. I feel like a god right now. Both were getting me close, but no cigar. Sweden kept avoiding infection or people were dying too quick. But, I finally got the persistent bastards.

  7. Shout out to Pan S Clock and Spicy for getting me going on the right track though!!!

  8. After trying multiple times with both guides I really don't get how they work for anyone. The last 100,000 die far too slowly and force me to go over 307 days. So aggravating. Guess I'll need to cross this one off my list...

    1. It should work keep trying! It didn't work the first time for me! Do to the random mutations of Smallpox it should only work 1 out of 5-10 times but it is better then the current method.

  9. i almost won it, the only land not infected was The Carribean.

  10. What happened to all the comments?

  11. We've recently changed comment platforms. Old comments are currently being imported but should take some time, they'll be back soon.

  12. Got 3 biohazard score with spicys guide, 305 days and 99% cure.

  13. Trying this strategy, so close several times. Confused on the vaccine shields, how you label them and all, I don't know which one is EJ7 and which one is EJ2?

  14. EJ2, EJ7, EJ13 are the names of the vaccine shields on the mobile version of plague inc. If I recall correctly, EJ2 will always be at the leftmost side, EJ7 will be at the middle, and EJ13 at the rightmost side.

    Do these vaccine shields have a different name on other versions of the game?

  15. Tried three times and each time was so different. Lol

  16. Got 3 stars with strategy 2 by not doing EJ7 vaccine. Doing blood earlier made me win with 96% cure. I suggest u delete this step.

  17. Been trying for six hours using the first strategy, finally cracked it! Managed it in 311!

  18. Almost, if it wasn't for the Canadians dying off :(

  19. Great! Worked on IOS using the 1st strategy, I got 3 Bio-hazard, in 306 days and 92% cure, after about 5 tries.

  20. I will have a guide bio-weapon brutal

  21. I used to have Greek letters as the vaccine names on Android. It recently switched to the EJs.

  22. 10 times fail from these strategies

  23. Excellent strategy Spicy. Coma was the first symptom to mutate in my 3 star scenario. Immediately after purchasing necrosis I bought Black Pox and started working my way up the tree from the right hand fork. I'd say it helped: 73481, 292 days.

    It was my second attempt.

  24. Used Spicy's strategy.

    Changed ATP Boost to Metabolic Jump.

    Cure percentage reached eighty seven.

    Three biohazards.

  25. We all can play with cheats mate.

  26. I was skeptical at the beginning but it did work on my first try with 79% complete, 322 days and 3 bio hazards.

  27. Tried this several times on Mega and failed... close but no cigar... either Greenland wouldn't infect and in one instance the Caribbean. So I went back to normal and tried and it worked... then stepped up to brutal and got close again.... Greenland was the stand out issue then noticed that the reason why Greenland wasn't infecting was because Russia and Norway (where the ships come from) are almost completely dead. Solution... once you have done Insect 1 and Formites 1... DEVOLVE fever... Fever kills can kill in cold countries and Russia and Norway would be deemed cold countries... these countries did not die out as quick so ships continued to sail... I tried it in brutal and it worked... went to mega brutal and first go 3 Biohazards.... Time 309 Days, Cure progress 71%, Score Total 70916.

  28. Tried this 10 times, my problem is not about getting to the island, its about the cure. People are smart man, I can't really waste the DNA for genetic hardening because It just can't keep up with it.

  29. First strategy is useless, ended up stranded with no DNA to evolve the vaccine shield, failed in 90 days

  30. Greenland and the Caribbean are not getting infected.

  31. I used Spicy's guide and finished in 327 days with the cure at 89% but only got 2 biohazards...