A man (Arie Verveen) is walking in the woods and comes upon a dog that he believes to be sleeping. After poking it a few times, he pulls the dog up and notices that his flesh is rotted, spurting blood on him in the process. The scene turns to five college friends, Jeff (Joey Kern), Marcy (Cerina Vincent), Paul (Rider Strong), Karen (Jordan Ladd), and Bert (James DeBello) who have rented a cabin in the woods. Along the way, they stop at a local convenience store for food where a young boy (Matthew Helms) outside the store bites Paul on the hand. When they arrive at the cabin, Jeff and Marcy immediately retire to their bedroom and have sex. Paul and Karen go for a swim in the lake while Bert goes hunting for squirrels in the woods. He accidentally shoots the man who discovered the rotting dog in the beginning of the film while hunting whom he mistook for a squirrel. The man's face has become badly rotted. Scared, Bert shoots at him again in order to repel him and runs back to the cabin. All seems to go well for a while. They build a bonfire and share ghost stories with each other. They soon encounter a local college kid named Grim (Eli Roth) who approaches them with his dog, Dr. Mambo. Though a little eccentric they allow him to join in when he offers them marijuana. However, once it starts raining, he leaves to take care of his camping equipment and the group retreats into the house. Later on, they hear a knocking at the door and discover it's the diseased man that Bert shot before. Desperate for help, the hermit comes after the group. He tries to drive away in their car, but vomits blood all over the windscreen and the seats of the car. After the man exits the car, Paul sets-light to the infected man and he runs aflame back into the woods where he dies in a lake.
In the morning, a young deputy, Winston Olsen (Giuseppe Andrews), shows up at the cabin and promises Paul he'll call a tow truck. Jeff and Bert come to a woman's house to ask for a ride into town. They soon discover that the woman was related to the hermit they killed so they leave quickly. During this time, Karen drinks a glass of water from the lake contaminated by the infected man and begins to feel ill. She goes to bed to rest. Paul later discovers rotten spots on her thighs. Karen is then quarantined in the tool shed outside. Fearing that they will soon also become infected, the others begin to argue with one another over what they should do about their situation. The next day, they discover Karen's condition is deteriorating fast. Bert also realizes that he himself is infected with the virus. Bert drives off to find a doctor. When Paul and Marcy insist on helping Karen, Jeff runs off into the forest with the remaining beer (the only reliable drinking source). Marcy yells at him as he flees, upset that he has abandoned her. Bert drives to the convenience store that the group visited earlier pleading for a doctor. He shows increasing signs of infection. The young boy on the bench then runs over and bites Bert, thereby infecting himself. His father (Hal Courtney) comes outside and, rather than helping Bert, tries to kill him. Bert speeds off and the father grabs two of his friends (Richard Boone and Tim Parati) who arm themselves with rifles to go after Bert.
Now alone in the cabin, Paul finds Marcy sitting despondently on her bed. He tries to reassure her, but she reiterates that they are all doomed to get sick, to the point where "all you want to do is grab the person next to you and (have sex with them), because you know you're gonna be dead soon, anyway." She seduces Paul and they begin having wild sex. Paul expresses concern that they aren't using a condom. Marcy brushes him off without heed by saying "Don't worry, I'm healthy!" and continues riding him. After they finish having sex, Paul worries about whether Marcy has the disease or not. He goes into the bathroom and attempts to disinfect his penis by pouring Listerine over it. While washing her face, Marcy discovers, with worry, some red marks on her back where Paul grabbed her in the heat of their sexual encounter. Later, Paul tells Marcy that he's going to bring back Jeff so that they can all walk back to civilization. Marcy urges him to stay, but Paul seems uncomfortable around her after sleeping with her and insists that he "has to get out of" the cabin. Now completely alone, Marcy has a bath and weeps. The marks Paul made on her back are shown to be developing into gruesome wounds like Karen's.
Paul heads over to the local reservoir, and notices a body floating in the lake. He climbs down the ladder and moves the body with a stick. He sees that it is the infected hermit. The dock's ladder rots and gives way, causing Paul to fall into the infected water, ensuring that he is definitely infected by this point. Marcy is shown shaving her legs in the bathtub and notices they are beginning to deteriorate. She runs outside, upset, and is attacked by a now infected Dr. Mambo. Paul returns to find Marcy's body ripped to pieces and Dr. Mambo eating a motionless Karen's face. Dr. Mambo attempts to attack him too. However, Paul kills him with Bert's rifle. Now alone, Paul goes to check on Karen whose skin has now almost fully rotted off; she is barely alive. To end her suffering, he clubs and impales her with a shovel and then runs for help. Bert struggles back to the cabin with the men in pursuit. When Bert's pursuers open the door, Bert tries to shoot one of the men but is killed by a shotgun round. Paul comes and successfully kills the store owner and his friends. After fleeing the cabin, Paul decides to look for Jeff. He checks a cave, thinking Jeff is inside, but only finds Grim's dead body.
Paul then runs back to Bert's pursuers' car and drives into town. Along the way he slams head-on into a deer, damaging the windshield and the car. He continues on foot until he comes to a party with Winston in attendance. He asks about the tow truck just as a police officer gets on the radio warning them about Paul and his group and that they are to be shot on sight. After all of the party attendees leave, Paul knocks Winston out with a stick. Paul is picked-up by a passing trucker and brought to the hospital. The sheriff and doctors interrogate him while he is lying in a hospital bed, trying to discover the source of the infection, but Paul is slightly dazed and unable to answer all their questions. When he is left alone, Paul pulls up his hospital gown to reveal the tell-tale marks of the disease on his belly. The doctors determine they are not equipped to handle the situation and that he should be transported to a larger, nearby regional hospital. His driver turns out to be Winston. Paul tries to warn him about the water in the reservoir but he can't speak well and only says "water". Winston says he will take him to get water. The next morning, Jeff comes out of the woods where he was hiding and makes his way back to the cabin. As he looks around, horrified that his friends are dead, he is suddenly shot to death by the police. They take his body and pile it on top of the others, which are burned in a fire pit.
While unconscious, Paul is dumped into a stream by Winston and left to die. Paul's body infects the water in the stream. Further down are two kids collecting water for their lemonade stand. They sell some lemonade to the sheriff, his deputies and more locals at the store. A natural spring water truck leaves the store with bottles of infected water in the truck.