Picking up one day after the events of the first Cabin Fever film, Paul (Rider Strong) wakes up in the creek surrounded by bloody water. He is severely infected by the mysterious flesh-disolving virus and he is covered in sores and boils. He begins walking through the forest as his skin begins to fall off. He makes it to the highway and is hit by a bus full of high school students, completely dismembering his body into an unrecognizable mess.Deputy Winston (Giuseppe Andrews), the cop from the first movie, comes to investigate the crime scene and tells the bus driver he hit a moose. The bus driver drives away to the high school. Winston finds Paul's foot in his shoe hanging from a tree. Winston, disgusted, drives away from the scene. He is informed by the sheriff over his CB radio to return to town for several "goverment guys" are there asking questions.Through an opening animation sequence, the creek Paul was lying in was connected to a bottled-water company and the infected water was distributed into bottles of water and brought to the high school of the kids on the bus.In the school, the lunch lady distributes the infected water for the kids to drink. John (Noah Segan), a senior at the high school, is deciding whether to go to prom with his long-time crush Cassie (Alexi Wasser) or stay home and watch a horror film with his friends. His overweight, social misfit friend, Alex (Rusty Kelley), is totally against going until he hooks up with a loose girl named Liz (Regan Deal). Eventually after Liz gives Alex oral sex, he asks Liz to prom. She then says she has to get off work and that she might meet him there.John asks Cassie to go to prom but Cassie refuses. He is convinced to go by Alex because Liz might go.Back at the small town, Winston is at a local diner where a worker from the bottled-water company that distributed the water goes into convulsions, coughing up blood, and dies right at his table from the infection. Winston then realizes that dumping Paul in the creek got the water heavily contaminated. Winston drives to the water plant and has one of the workers there tell the officials that the water is contaminated. Just as Winston leaves, the worker is killed by a group of CCD (Contamination Control Division) soldiers who show up in U.S. Army trucks to quarantine the whole town and they have orders to kill anyone who might be infected to prevent the virus from spreading.At the high school, the infection begins to spread to the students. Rick (Thomas Blake Jr.), a popular student, ditches his girlfriend, Sandy (Lindsey Axelsson), the school's popular and mean girl, right at the prom. He meets and seduces an over-weight student, named Fredricka (Amanda Jelks), because of a bet with his jock friends. She had just finished making a punch with the contaminated water. They go to the gym swimming pool and begin to have sex in the pool. She then begins to succumb to the infection. Rick panics and gets out of the pool. Fredricka screams as she begins to drown for she can't swim. Rick tries to save her by using a pool strainer. She pulls on it and pulls Rick in. He hits his head on the side of the pool and bleeds to death. Fredricka drowns.At the prom, Alex is disappointed that Liz did not show up at all. Mean girl Sandy complains to Principal Sinclair (Michael Bowen) that she can't find Rick and screams that since she is the prom queen everything should go her way. Ms. Hawker (Angela Oberer), a mean teacher at the school, then slaps Sandy. John finds out Cassie is there with her boyfriend Marc (Marc Senter) who John hates. The two begin to fight. The principal splits them apart and kicks John out of the prom, blaming him for starting the fight. Cassie follows him outside trying to calm him down. John confesses his love to Cassie who does not know who to react. Just then, CCD soldiers in haz-mat suits arrives in U.S. Army trucks, and force John and Cassie to go back into the school. The CCD locks all of the main exits from the school and tells them that a quarantine is in effect. The two become worried and go back to the gym to warn the principal of the lock down. They go through the pool where they find Fredricka's rotting body floating in it.They find the principal and get Alex out of the gym. The principal demands to know what is going on with the lock down but the CCD soldiers shoot him in the head, killing him. The infection then begins to spread and kill the students in the gym at an alarming rate. The gym is then gassed from the outside by the soliders who then storm into the building to kill the infected. Cassie, John, and Alex watch in horror as the students try to get out of the gym but to no avail. All the students including Sandy die in the gym from the poison gas or by getting shot by the soldiers.Meanwhile, Winston is waiting outside a liquor store and is picked up by his cousin Herman (Mark Borchardt) who is at first reluctant about leaving town to escape from the quaratine, but Winston convinces him by giving him a grin (implying that they are going to Mardi Gras).Back at the school, Cassie, John, and Alex try looking for an exit. Alex storms off after finding out he is infected with the disease. He goes to the library to find out what it is. Cassie and John decide to go out through the auditorium.They try to find Alex while evading the CCD soldiers who are wearing bio hazard equipment. They find an infected Ms. Hawker who is killed by a soldier. They go to the library were they find Alex. They also discover that the disease is necrotizing fasciitis and incurable. Alex says the only way to stop the infection is to cut off the limb the infection is on. He dies moments later with John and Cassie distraught. John finds a boil on his hand and he knows he is infected with the disease. He and Cassie go to the wood shop room where Cassie cuts off John's hand with a buzz saw to stop the infection from spreading and uses an acetylene torch to stop the bleeding.Meanwhile, Winston and Herman are near the city limits when a police roadblock prevents them from going any further. After failing to convince the officer to let them leave, Herman knocks him unconscious and they drive away.Cassie's boyfriend, Marc, then comes out of nowhere and tries to kill John. Cassie kills Marc with a nail gun. John and Cassie leave the school only to be ambushed by the CCD soldiers who open fire on them. John stalls them allowing Cassie to escape from the school area through the woods behind the school. John is captured and is taken away by the CCD apparently to quaratine him as well. Cassie finds herself on a local road and stops Herman's van. Winston and Herman take away Cassie with them, not knowing she is infected with the virus.The end of the movie shows Alex's date with Liz at her work place. She is a stripper at a strip club (she lies about her real age). She is also infected and she secretly has sex with a customer at the club. He then becomes infected and begins to spread it around his work office the next day through the smallest casual touch. His friend, who had sex with her co-worker, also becomes infected, spreading to others on his trucking route to New Orleans along with two Mexican men who go back to Mexico also infected. The flesh-disolving pandemic is now spreading to global proportions. The infected Liz then goes home sick and wishes she went to prom instead of work.After the credits, John's friends, Daryl and Dane, (the only ones clearly not infected) are shown watching a movie at home and Dane says "prom blows."