It's been ten years since FBI agent Clarice Starling (JULIANNE MOORE) interviewed convicted serial killer and admitted cannibal Hannibal Lecter (ANTHONY HOPKINS) while searching for another killer. After assuming responsibility for a botched drug bust that resulted in her shooting the suspect who was holding a baby, Clarice is on the hot seat. About to be punished by Justice Dept. official Paul Krendler (RAY LIOTTA), she gets a reprieve when Mason Verger (GARY OLDMAN), a wealthy and influential recluse, asks that she be put back on the Lecter case and that the killer, who's been on the lam for the past decade, be reinstated on the FBI's ten most wanted list.
It seems that Verger was Lecter's only victim to have survived, but with a terribly scarred face and a life sentence in a wheelchair. Verger apparently has some new evidence about Lecter, so Clarice goes to interview him, and then does the same with Barney (FRANKIE R. FAISON), a former guard who knew Lecter for many years and is in possession of many audiotapes of the killer's thoughts.
Meanwhile in Florence, Italy, Inspector Rinaldo Pazzi (GIANCARLO GIANNINI) is investigating the mysterious disappearance of a curator and thus goes to question the man's potential replacement, Dr. Fell, who turns out to be none other than Hannibal Lecter.
Once Pazzi realizes who Fell really is, he sets out to collect evidence to prove that and collect a handsome reward, all while Clarice tries to pinpoint the origin of a letter she received from Hannibal that stated it was time for him to get back into the limelight. From that point on, and as Verger decides to use Clarice to lure in Lecter so that he can get his revenge on him, the various involved parties try to find the killer who always seems to be one step ahead of their plans and thinking.