The film opens in 1974 at the Glenville Sanatorium for the mentaly ill with Dr. Ryan (Arne McPherson) showing a local psychiatrist Dr. Ann McQuaid (Kristen Harris) around the psychiatric hospital. The cannibals from the previous films-One Eye, Three Finger, and Saw Tooth now are locked up in the institution as children. But the cannibals escapes and sets other insane patient free in the hospital. Then cannibals savagely murder an orderly, a guard, Dr. Ryan and Dr. McQuaid.
The film then switches to present day (in 2003) where a group of nine college kids; Kenia (Jennifer Pudavick), lesbian couple Sara (Tenika Davis) and Bridget (Kaitlyn Wong), Lauren (Ali Tataryn), Jenna (Terra Vnesa), and Claire (Samantha Kendrick), along with their guy friends Kyle (Victor Zinck), Vincent (Sean Skene) and Daniel (Dean Armstrong) are going snowmobiling. They are heading to their friend Porter's cabin in the mountains. They get lost in a storm and seek refuge inside the now abandoned Glenville Sanatorium. Little do they know, the three now adult cannibals are hiding out in the sanatorium and murdering trespassers (The movie is silent about whereabouts of rest of patients set free by cannibals). The group of teenagers explore the asylum, and decide to wait out the storm. After a montage of rolling around in wheelchairs, acting on illegal drugs, drinking booze and acting like teenagers, the storm still hasn't stopped so the teenagers are forced to sleep in the desolate building. In the middle of the night, Vincent, suffering from insomnia, walks around the asylum and finds Porter's mutilated body - apparently he didn't make it to his cabin either.
He is then killed by Saw-Tooth having a metal rod shoved into his chin and out through the top of his head. The next morning, everyone discovers they are still snowed in, and Vincent is missing. The gang splits up to look for him, and Jenna witnesses the cannibals cutting Porter up. She runs back to tell the others and they all meet up in the auditorium.
Something wrapped in Porter's jacket is thrown at them and Kenia opens it up to reveal Porter's severed head. Screaming and panicking, the group flocks around the door, trying to get out but the doors are locked. The three cannibals, up in the balcony, throw down a strip of barb-wire and loop it around Claire's neck, pulling her up to the balcony. Kyle tries to save her, but it is too late and the barb-wire tightens, severing Claire's head. Horrified, those who are left of them (Kenia, Sara, Bridget, Lauren, Jenna, Kyle and Daniel) run outside and try to escape on their snowmobiles, but the engines won't turn and it is revealed that the cannibals had stripped them of their spark plug wires. Lauren sets off on her own to ski down the mountain to retrieve help and the other six run inside to try to defend themselves. Kenia, Bridget, Sara, Jenna, Kyle and Daniel barricade themselves in an office where they find files on the three cannibals that say the three are deformed and cannibalistic.
Sara, armes herself with a fire poker. Daniel and Kyle leave to go find more weapons with Kyle remembering the room filled with knives and saws that him, Kenia, Claire and Jenna found while they were searching for Vincent. The three are chased by Three Finger who is also wielding an axe and they find the room filled with knives, lock themselves in and hide, waiting for him to pass. Meanwhile, One Eye attempts to break through the door of the office with a drill but Kenia, Bridget and Jenna fend him off.
Back with Sara, Kyle, and Daniel, they stock up with an arsenal of knives and other tools, and run back to the others, but on the way Daniel is grabbed by the cannibals and dismembered with a knife. Sara, Bridget, Kenia, Jenna and Kyle go to look for Daniel after hearing his screams. The cannibals are slicing off pieces of Daniel's skin and cooking them in a pot of boiling oil. Kyle is separated from everyone else and discovers the killer clan torturing Daniel. The teenagers devise a plan to catch the cannibals and succeed in trapping them inside a cell. Kyle attempts to set them on fire, but Kenia coaxes him into having the heart and not killing them. Sara, Bridget, Kenia and Jenna go to search for the spark plugs that were stripped from their snowmobiles earlier, and Kyle stands guard outside, but Three Finger manages to pick the lock to get the cell open and Saw Tooth grabs Kyle by the throat and delivers one punch then the screen goes black. Kenia goes to check on Kyle and finds him and the cannibals gone.
She runs back to the office with Sara, Bridget, and Jenna and the four girls decide to stay in the room until morning. One of the cannibals appears wearing a potato sack, and the girls stab him to death only to reveal it is Kyle whose tongue was cut out so who couldn't talk and they just mistakenly killed him. The girls then encounter the three cannibals and are chased up into the attic. They find some old winter clothes and put them on and then run back down to the main floor and try to escape through a window.
To their dismay, they are all grated, except for one where the grate is bent. Sara rips away the grating and shatters the glass and the girls climb through the window and out into the snow. But Jenna-who climbs through last-doesn't make it and is killed with a drill. Kenia, Sara and Bridget run away into the snow pursued by the cannibals on the teenager's snowmobiles. Bridget is captured, but escapes using her knife to stab one of the killers in the arm.
Kenia is wounded, and Bridget is killed. Morning starts to come, and it is revealed that Lauren had frozen to death, just a few yards from a road. It switches to the cannibal chasing Kenia on the snowmobile, but Sara hits him with a log. The two then board the snowmobile and drive off into the snow--but they run into a barbwire fence and are both decapitated. Three Finger then appears, grabs the girl's heads, throws them into the back of the yellow tow truck that appeared in the first film. Three Finger Hops in himself and he and the other cannibals drive off and the film ends.