Henry Fonda originally turned down the role of Frank. Director Sergio Leone flew to the United States and met with Fonda, who asked why he was wanted for the film. Leone replied, "Picture this: the camera shows a gunman from the waist down pulling his gun and shooting a running child. The camera pans up to the gunman's face and...it's Henry Fonda" (until then, with one exception, Fonda had only been cast in "good guy" roles. Leone wanted the audience to be shocked).
Sergio Leone liked to tell the story of a cinema in Paris where the film ran uninterrupted for two years. When he visited this theater, he was surrounded by fans who wanted his autograph, as well as the projectionist, who was less than enthusiastic. Leone claimed the projectionist told him "I kill you! The same movie over and over again for two years! And it's so SLOW!"
Al Mulock, who played one of the three gunmen in the opening sequence, committed suicide by jumping from his hotel window in full costume after a day's shooting. Claudio Mancini and Mickey Knox, who were sitting in a room in the hotel, saw Mulock fall past their window. Knox recalled in an interview that while Mancini put Mulock in his car to drive him to the hospital, director Sergio Leone said to Mancini, "Get the costume! We need the costume!" Mulock had appeared as the one-armed bounty hunter in Leone's Três Homens em Conflito (1966), and he was wearing his costume from that film when he made his fatal leap.
Claudia Cardinale's first day of filming was her nude love scene with Henry Fonda. This also marked the first time Fonda had done such a scene. His wife insisted on being on-set during the filming of it.
Henry Fonda prepared for his role as the villain "Frank" by arriving in Italy with a pair of brown colored contact lenses and a mustache. When Sergio Leone saw them, he ordered them removed. Leone had planned an important close-up shot of Frank's entrance and wanted the audience to instantly recognize Fonda with those blue eyes.
Luana Strode: The Indian woman who flees from the train station in the opening sequence. She was the wife of Woody Strode.