A hermit walking in the woods encounters his dog, who has died of a blood infection, and the hermit becomes infected. Meanwhile, college students Jeff, Marcy, Paul, Karen, and Bert take a vacation to a remote cabin to celebrate spring break. Bert leaves to shoot squirrels but shoots the now disfigured and bloody hermit. Despite the hermit's pleas, Bert flees and remains silent about the incident.
The group gathers around a campfire that night, where they are joined by a friendly drifter named Grimm and his pet dog, Dr. Mambo. When it rains, Grimm leaves with his dog to pack up his belongings. While the friends wait for Grimm indoors, the hermit returns, begging for help. When Bert shuts the door on the sick hermit, he tries stealing the group's car while vomiting blood. When the hermit approaches Marcy and Karen, Paul accidentally sets him on fire. While seeking help the next day, Jeff and Bert encounter a butcher but leave after learning she is the dead hermit's cousin. Paul receives assistance from police Deputy Winston, who promises to send up a tow truck. Paul tries comforting Karen, who is upset over the killing of the hermit. After calming her down, Paul attempts to have sex with her; as he reaches between her legs, he discovers an infection that has spread in her groin. The group isolates her in a shed.
After fixing the truck, Bert coughs up blood but does not tell the others. Bert drives off after Paul and Jeff discover he has caught the disease. Jeff takes the remaining beer and leaves, terrified of becoming infected. Bert seeks help at a convenience store but angers the owner after his son, Dennis, bites him. Bert flees, chased by Dennis's father and two friends. At the cabin, Marcy worries that they will all contract the disease. When Paul comforts her, they impulsively have sex. Regretting the affair, Paul leaves while Marcy takes a bath, crying; as she shaves her legs the flesh begins to peel off and she runs outside in a panic, where she is eaten alive by Dr. Mambo.
Paul discovers the hermit’s body floating in the reservoir, and realizes the infection is spreading through the water supply. Racing back to the cabin, Paul finds Marcy's remains and Dr. Mambo feeding on Karen. After killing Dr. Mambo with Bert's gun, he bludgeons Karen with a shovel out of mercy. A dying Bert returns to the cabin pursued by Dennis's father and his two companions. The posse shoots and kills Bert, and Paul kills all three of them. Paul looks for Jeff; he instead finds Grimm's corpse. Paul takes the convenience store's truck, and, while driving, discovers he is infected before hitting a deer. He reunites with Deputy Winston, who is partying with underage drinkers. Paul requests a ride to the hospital, but before the group departs, Winston is ordered to kill on sight several infected people on a killing spree. With the group turning on him, Paul attacks and infects several of Winston's friends before knocking Winston out. A passing truck drops off Paul at a hospital, where he weakly discusses where he caught the disease. The doctors inform the sheriff that Paul must be transferred. Lying in the back of Winston's squad car, Paul unsuccessfully warns him about the contaminated water supply; Winston dumps him at the edge of a creek.
Jeff, who has been hiding out and drinking in the woods, returns to the cabin the next day. Initially crying after seeing the remains of his friends, he becomes ecstatic upon realizing he is the only survivor. As he raises his arms in victory, Winston shoots him and burns his body with the others. At the convenience store, several children sell lemonade, which they have made with the water from the creek Paul was dumped in, to the same police officers. A large truck filled with bottles of water taken from the creek can be seen leaving the store.
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