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With no excercise and eating loads of junk food, Frank (Murray) is not taking care of himself. And although he doesn't realize it, there is a whole population living inside him that depend on his health.

In The City of Frank, lives millions of blood cells. Among them is Osmosis Jones (Rock), a sarcastic, street-smart white blood cell and an officer of the FrankPD. When an evil virus named Thrax (Fishburne) enters Franks body, it's up to Osmosis to hunt him down. Meanwhile, Frank's daughter has become concerned for his health, and gives him some cold medication, which provides Osmosis with a partner, Drix (Pierce).

Unfortunately his new by-the-book partner, Drix has only twelve hours of time-released germ-fighting power, so they must work quickly to find Thrax and get him out of Frank's system.