Frank Detorre is a widowed slovenly zookeeper at the Sucat Memorial Zoo in Rhode Island. Much to the frustration of his young daughter, Shane , he eats compulsively unhealthy and has minimal concern for germs or disease. While trying to eat a hard-boiled egg with mayonnaise and salt, it is stolen from him by a chimpanzee. He gets it back, but not before it falls into the filth of the chimp's habitat. When Shane is disgusted by him about to eat it he uses the "ten second rule" as a justification for the unsanitary act.Inside Frank's body, Osmosis "Ozzy" Jones, an agent of the Frank PD, is an adventure-seeking white blood cell with a good sense of humor. He is a rebel cop, frequently disobeying authority to do what he thinks is right. He is often mocked by his fellow cops due to his rebellious nature. He has been relocated to the mouth to fight against germs entering the body via ingestion after he induced Frank to vomit all over Shane's science and P. E. teacher, Mrs. Boyd at the school's science fair. This was considered a false alarm because he had been the only one to suspect an incoming pathological threat from the raw oyster Frank had eaten from one of the displays. After several newcomer germs, believed to be gingivitis, hijack a "squad car" in the mouth, Osmosis and another officer in an FPD helicopter, are pulled into the lungs by a massive yawn while in pursuit. After the germs evade capture and pass into "Immunity's" jurisdiction, Osmosis disobeys direct orders as he pursues the germ on foot and accidentally triggers a major cramp in Frank's leg.Meanwhile, Mayor Phlegmming is preparing for re-election, campaigning with the promise of more junk food. His reckless policies are largely responsible for Frank's deteriorating health, but his re-election hopes are complicated by the arrival of Thrax, a deadly virus that came with the hard-boiled egg. In an attempt to cover up the severity of the situation, Phlegmming "tells" Frank to take a cold-suppressant pill. The pill, Drixenol "Drix" Koldreliff, arrives in the body and covers Frank's infected throat with a disinfectant to soothe the irritation. Osmosis is assigned as Drix's partner, much to their mutual chagrin. Later on, an influenza virus tells Osmosis and Drix about Thrax's plot to masquerade as a common cold while at the same time plotting to kill Frank with a high fever. Osmosis and Drix confront Thrax in a club in one of Frank's zits, where Drix launches a grenade of medication at Thrax and his goons, popping the skin blemish, killing nearly all of Thrax's men, and seemingly ending the virus's siege. The pop of the zit further aggravates Mrs. Boyd, when Frank comes to apologize for his earlier action of vomiting on her at the science fair.Thrax survives the explosion and after killing off his remaining henchmen, launches a lone assault on Frank's hypothalamus gland (the portion of the brain that controls the temperature) by disabling its self-regulative capabilities. There, he uses his virus-infecting claw to destroy the protoplasmic barrier around the gland and takes a DNA bead. Soon after, the mayor's secretary, Leah Estrogen, discovers his sabotage and alerts security. Thrax manages to evade them, taking Leah hostage and escapes from the brain to the mouth. Meanwhile, the temperature continues to rise, causing chaos to break out all over the City of Frank. Frank is taken to the hospital under the influence of Thrax's attack. Ozzy and Drix rescue Leah and confront Thrax, who leaves Frank's mouth after causing confusion using pollen. Osmosis and Thrax fight on one of Shane's eyeballs and end up on Shane's false eyelashes after she blinks, which she was wearing atop her natural ones on her way to a hiking trip.During the fight, Thrax threatens to kill Shane, but Ozzy causes him to knock Shane's false eyelash into a vessel of alcohol below, where he dissolves. During this time, the situation becomes even more dangerous when the temperature hits 108 degrees Fahrenheit, causing Frank to go into cardiac arrest. Just as doctors give up, Frank is revived when Ozzy returns to his body with one of Shane's tears with the missing hypothalamus chromosome. Ozzy is reinstated into "Immunity" with full privileges, he and Drix are declared heroes with the Chief of Police giving Ozzy his job back. Having survived Thrax's attack, Frank has begun to improve his diet and personal hygiene.Meanwhile, Phlegmming has lost his position as mayor and is now a janitor in the bowels. He accidentally ejects himself from the body via the rectum by touching a button that is important and marked "DO NOT TOUCH!" which triggers Frank's farting.