Frank Detorre is a slovenly zookeeper and widowed father to his daughter, Shane. He catches a cold right after he swallows a germ-ridden egg. The inside of his body is known as the "City of Frank". An unlikely hero of a white blood cell named Osmosis Jones works as a member of Immunity cell. But with that egg comes a mortal danger: Osmosis discovers that Frank has really contracted a villainous and black-hearted deadly virus known as Thrax who arrives and is plotting to ultimately overheat his body, killing him from the inside out. Thrax is motivated by trying to become the nastiest new virus, attempting to kill each new victim faster than the previous ones. His grandiose plan for Frank is death in 48 hours, breaking previous medical records. Meanwhile the cold pill that Frank took, Drix, arrives in his body and covers his throat with ice to cover the irritation. Osmosis becomes his newest partner. Now it's all up to them to put an end of Thrax's plans before Frank dies and Shane becomes an orphan.