Dean: A demonic virus?
Sam: Yeah, more like demonic germ warfare.
– Sam and Dean Winchester, 2.09 Croatoan
Croatoan is an ailment specifically described as a "blood-borne virus" that is demonic in origin, and causes a murderous rage in the people it infects. One legend uncovered by John Winchester states that the virus was the source of the disappearance of the Roanoke Colony in 1587.
Azazel field tests the virus in River Grove, Oregon in 2006. It proves effective in causing the townspeople to kill each other, and importantly proves that Sam Winchester is immune to its effects. It is unknown what happens to the infected, but they were most likely killed by demons as releasing the virus was part of the field test.
Following his release, Lucifer intends to use this virus to produce chaos and mass genocide on Earth during the Apocalypse. The virus is to be distributed by Niveus Pharmaceuticals in a vaccine that is reportedly being used against a swine flu epidemic caused by Pestilence. The plan is averted when Castiel, Sam, and Bobby destroy the warehouse where the vaccine is stored.
The Croatoan Virus leaves behind traces of sulfur in the bloodstream after a three hour incubation, after which symptoms begin to surface. Infected people display a murderous rage and a sociopathic change to their personalities, eventually regressing into a more animalistic state and displaying no instinct. They also work together in packs and are able to recognize if someone carries the virus as they only target people who have not been infected. When the virus spread throughout the population of River Grove, everyone who got infected disappeared within a day, leaving only the survivors, and any possible blood samples taken by the infected victims leave no trace of the virus afterwards. It is unknown if there is a cure for the virus, however people with demon blood in their system, such as Sam Winchester, are shown to be immune to infection, showing no traces in his blood stream after five hours following contact.
By the time the Apocalypse started, Pestilence and his demons had been working to mutate the virus, causing the infected to display symptoms almost immediately. Unlike previous victims, they displayed bloodshot eyes and become more feral than average croats, attacking anyone on sight.
Following a vision of Sam's in which Dean shoots a man, Sam and Dean travel to River Grove, Oregon. In searching for the man from the vision, they encounter his mother, who is being held by his brother and father, both of whom are overcome with a murderous rage. Sam and Dean save the woman from her son and husband, but it soon becomes clear that she is infected, and Dean kills her. The brothers retreat to a local clinic, where Dr. Amanda Lee studies the blood of an infected person and notes that there appears to be traces of sulfur present, leading Sam to suspect demonic intervention. The virus is transmitted via an exchange of blood, and it takes between three and four hours for symptoms and the sulfur to manifest. The infected show a planning ability and use weapons. They also deliberately infect others.
Sam speculates that the virus could be related to a theory in John's Journal, that Croatoan - a word they find carved into a telephone pole - is the name of a demon associated with plague and pestilence. Sam calls what's going on "demonic germ warfare."
I've been pawing through Dad's journal, I found something about the Roanoke Colony. Dad always had a theory about "Croatoan." He thought it was a demon's name, sometimes known as "Deva", sometimes "Resheph", a demon of plague and pestilence.
Duane Tanner, the man Sam saw in his vision and whose family Sam and Dean first encountered exhibiting signs of infection, turns up at the medical center. He claims to have been out of town fishing and to have just returned. The medical center occupants suspect he might be infected, and they restrain him by tying him to a chair. Recognizing the scene from his vision, Sam tries to convince Dean not to kill Duane Tanner, as they don't know yet whether he's infected with the virus or not. Dean locks Sam in a room so that he cannot interfere, but Dean is unable to follow through and kill the man. He releases Sam, and they work on an escape plan.
The nurse Pamela Clayton deliberately infects Sam, and he resigns himself to dying, but he shows no symptoms. Five hours later, the doctor announces that there is no trace of the virus in Sam's blood. The previously collected blood samples no longer have any trace of the virus and all the remaining townsfolk have disappeared.
At the end, Duane Tanner - who is revealed to be possessed - is shown communicating with Azazel via a goblet of blood, and reports that "the Winchester boy is immune" (to the virus). Because Sam's vision led them to River Grove, it's implied that this "demon virus" is the work of the Yellow-Eyed Demon.
5.04 The End
In this alternate future, Lucifer releases the Croatoan virus in order to wipe out humanity. In 2012, the virus started hitting the major cities, causing the human population to drop dramatically. By 2014, many have been infected and died while only a handful of people remain alive. Infected zones are quarantined and the military kills the infected, referred to as "croats" on sight. President Palin orders the bombing of Houston following an outbreak.
In 2014, Future!Dean leads a small group of survivors, and is trying to locate and recover The Colt to kill Lucifer. When one of his men becomes exposed to the virus, he shoots him without warning, later telling Dean that he started recognizing symptoms a half hour prior to his death. When Future!Dean locates Lucifer, Future!Castiel points out that it's in the middle of a quarantine zone infested with croats. However, no croats appear when they arrive, making Future!Dean realize that the demons cleared a path for them, preparing a trap for the hunters.
5.20 The Devil You Know
Two scientists are discussing the ongoing swine flu epidemic and the vaccine being developed. A demon possessing a janitor tells them he's seen the vaccine, and that he is running an experiment of his own. He injects a sample of the vaccine into one of the scientists and knocks the other down, then he darts out the door and locks them in the room. The scientist injected with the "vaccine" rises, then attacks and kills the other scientist. The demon janitor calls someone else, and states that "it works." It is suggested that it is the Croatoan virus, and that the plan for distributing it during the epidemic as a vaccine is orchestrated by Pestilence and his demons. A demon named Brady, installed at Niveus Pharmaceuticals is responsible for production.
Unlike the infected in 2.09 Croatoan, these victims are immediately overtaken by the virus. They show no higher intelligence, only a fierce anger and drive to attack others. This suggests that the demons have worked to improve the lethality of the virus.
5.21 Two Minutes to Midnight
It is revealed to Sam and Dean that Niveus Pharmaceuticals is distributing a vaccine for the swine flu epidemic, which is actually the Croatoan virus. Sam, Castiel and Bobby rush to the warehouse in order to stop the distribution. The demons infect a number of human workers in the warehouse in order to stop them, but the infected are quickly dispatched by the joint efforts of Sam, Castiel and Bobby. The three of them blow up the warehouse afterwards to destroy all the vaccine and any traces of the virus.
- Fandom celebrated August 1, 2014 as Croatoan Day, commemorating the spread of the Croatoan virus as depicted in 5.04 The End. Fans wrote "Croatoan" on their arms, and hoarded toilet paper; a disappointing few donned pink panties. Check out some of the photos here.
- During the COVID-19 outbreak, Eric Kripke posted a tweet where Sam and Dean believe that COVID-19 is the Croatoan Virus.
- The Croatoan Virus is considered to be a demon mutation.