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Sir Anthony Hopkins (Dr. Hannibal Lecter), Anthony Heald (Dr. Frederick Chilton), and Frankie Faison (Barney Matthews) all reprised their roles from earlier movies in the franchise. Faison is the only one to have appeared in the first four Thomas Harris "Hannibal" adaptations, having also appeared in Manhunter (1986) in a different role.
Sir Anthony Hopkins stated that one of his goals in playing Dr. Hannibal Lecter for a final time was to re-establish that he is an evil serial killer, as Hopkins believed Hannibal had come to be seen too much as a likable anti-hero by audiences.
Sir Anthony Hopkins showed up on the set during one of his off days just so he could watch Philip Seymour Hoffman work. The two actors shared no scenes in this movie.
After this movie's release, Sir Anthony Hopkins said this would be his last portrayal of Hannibal Lecter.