Five teens: Paul (Rider Strong), Karen (Jordan Ladd), Bert (James DeBello), Marcy (Cerina Vincent), and Jeff (Joey Kern) go for a week-long vacation to a secluded cabin in the woods. While there, they meet Justin (director, Eli Roth) and his dog. Later that night, they are approached by a man with a skin disease who asks for help. They refuse to help him, and after he tries to steal their car to drive to the hospital, they end up lighting him on fire and watch him run into the woods. Their car is destroyed in the altercation.
The next day, Karen gets sick, and soon she is covered by the flesh-eating virus and locked in the shed outside. The teens also are stalked by Justin's dog, who apparently has escaped from Justin and is starving and/or rabid. The group is unable to get any help from the neighbors, and quickly begin fighting with each other. Jeff runs off int the woods with all the beer, and Bert manages to start the car and drives in to town. Marcy and Paul end up having sex, and both discover that they too now have the skin disease. Paul wanders into the woods and finds that the man they set on fire ended up falling in to the town's reservoir, and the flesh-eating disease is being spread through the drinking water. He also discovers that Justin has died. Meanwhile, the townspeople are disgusted by Bert's condition (he has also caught the disease) and blame him for bringing the disease to the town. They chase him back to the cabin in order to kill him and his friends. In the mean time, Karen is mercy-killed by Paul, and Marcy is eaten by Justin's dog before Paul kills it. During the altercation with the townspeople, all are killed except for Paul and Jeff (who is still drunk in the woods). Paul is eventually found by a truck driver and taken to the hospital, but is too delirious to tell them what happened at the cabin or how he got the disease. Paul is then taken from the hospital and thrown by a deputy into the town's spring, presumably to die there (in Cabin Fever 2, we discover that Paul is not dead yet).
Jeff, having finally sobered up, stumbles back to the cabin where he is killed by the sheriff. The sheriff burns the bodies and the cabin to the ground. He and his deputies then go back to town and buy some lemonade made with infected water. After the credits, we see an 18-wheeler transporting a large shipment of bottled water from the town's infected reservoir.
Order of main character deaths: