- Fake Nationality: Charlton Heston plays Italian renaissance painter Michelangelo. Some of the other Italians are played by Rex Harrison & Harry Andrews (both English), Diane Cilento & John Stacy (both Australian), and Tomas Milian (Cuban-American); though Cilento did have Italian ancestry.
- Gay Panic: Charlton Heston refused to allow scenes from the movie to be shown in the documentary The Celluloid Closet because he believed Michelangelo was straight and played him as such. Then again, if the screenwriter felt otherwise, it wouldn't be the first time Heston played a crypto-gay character without realizing it.
- Hostility on the Set: Rex Harrison did not get along with Charlton Heston at all during filming, though not necessarily a bad thing for two actors playing antagonists. Twelve years later, while filming Richard Lester's adaptation of The Prince and the Pauper, he avoided Heston completely.
- Scully Box: In his autobiography Rex Harrison admitted wearing lifts in the film so he would look more in line with Charlton Heston.
- What Could Have Been:
- The movie was originally supposed to have been filmed in 1961, starring Burt Lancaster, but production was delayed for three years.
- Laurence Olivier was the studio's first choice to play Pope Julius, but was unavailable. Spencer Tracy was also offered the role.
- Michelangelo would go on to complete The Last Judgment - the fresco on the wall behind the chapel's altar about twenty-five years after completing the ceiling.
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