Sometime after the events of Cabin Fever (2002 film), a very disfigured Paul (Rider Strong) escapes from the creek and wanders through the woods, leaving pieces of his own flesh along the way. When he finally manages to make it to the highway, he is splattered and killed by a school bus. His remains are checked by Sheriffs in the United States Winston Olsen (Giuseppe Andrews), the local policeman from the previous film. Winston assures the shocked bus driver that he had hit a moose.
Dr. Edwards arrives at a secluded island laboratory to examine Mr. Porter. Although Porter carries a deadly flesh-eating virus, he is asymptomatic and shows no signs of necrosis. Along with fellow researchers Camila and Bridget, Dr. Edwards spends two months examining Porter in isolation. Porter continually asks to see his wife, but he is continually denied.