The fourth grade class won’t be denied their rights as children to make fun of the unfortunate kid who has lice.
Confidentiality about who has head lice must be maintained so no child is embarrassed; so says the administration at South Park Elementary . When Garrison refuses to name names, Eric Cartman finds a way to detect who has the head cooties.
Everyone is called to the gymnasium for hair lice inspection. Clyde discovers he is suffering from it and has to visit a doctor who prescribes a special shampoo.
In the lice's world, a louse called Travis Mayfield informs the President that they may be facing a problem, believing that the world (Clyde's head) might be reacting to their activity, and that there should be a lice-wide evacuation. The Vice President Greg, however, rejects Travis's claims, and orders him out. Later, it starts raining (Clyde showering), but Travis perceives the event as an omen, and insists for his wife Kelly Mayfield and their daughter Hope to run. Some other lice notice a substance (special shampoo), and quickly find out it will kill them from continuous exposure.
Soon they begin to die in the acidic shampoo. Travis, Kelly, and Hope flee to the trees with other lice. They do avoid the shampoo, but then a large gust of wind (Clyde drying his hair), knocks many of them off towards the ground below. As the wind blows, Kelly's arm breaks and she falls to her death along with many others, leaving Travis alone with Hope.
The next day, Cartman asks Ms. Garrison who had lice, but she will not say. Class ends, and the students suspect their classmates, prompting Cartman to discover a way to find out who it was.
Few lice survive, but most of them decide to stay while Travis, Hope, a female louse, and the Vice President make their way into "The Forbidden Zone" (Clyde's face) in hope that from there they can travel to another world.
Cartman invites the boys for a test (which doesn't actually work) that later suggests Kenny McCormick had the lice because he is poor. Kenny runs for his life out of the school.
At Clyde's house, the boys tell Clyde they're going to sock bath Kenny (washing him with wet soap and drying him off with dirty socks) and that he should come. Clyde says he'll come in a minute. As the boys leave he phones Ms. Garrison and tells her what's going to happen.
The female louse is shot in the head and Travis is shot in the knees upon entering "The Forbidden Zone" (the back of Clyde's neck) by the Vice-President (he had a micro-sized Glock 17), who then - to prove his point - shoots the ground six times, saying, "If the world were conscious, it would feel this". Next thing he knew, Clyde's fingers grabbed him and threw him onto the sidewalk, as Travis muttered a low, crying laugh, effectively disproving the Vice President's laugh.
At the park the boys prepare Kenny for the sock bath when Kyle Broflovski stops them and tells them it was him who had the lice. Stan Marsh is surprised since he thought he was the one. Then, even Cartman reveals he had lice and he was trying to frame Kenny. Ms. Garrison arrives and explains to them how quickly lice spread. Regardless, all the students (except Clyde) give Kenny the sock bath anyway, as a punishment for lying about his case of lice (although the whole thing was Cartman's fault).
As Travis lays dying a fly lifts him up and takes him to a new place where bigger red lice are, where they have lived in peace for "generations". They help Travis and Hope and welcome them to their land. It soon turns out this place is Angelina Jolie's pubic hair and the lice were crabs.