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 and Leone wanted the audience to be shocked. When the film was first shown on US television, the moment where Frank shoots the little boy while smiling wasn't shown because American executives didn't think the public would be able to handle Fonda doing something so evil on screen.
The previews for the film in the US were a disaster. People found it too slow and too long, so much to the disgust of Sergio Leone, roughly twenty minutes of the film was cut. The scenes removed included Jill, Harmonica, and Cheyenne first encountering each other at the tavern. So Lionel Stander who played the bartender was in the credits but not actually in the film, and Cheyenne wasn't first seen until he shows up and confronts Jill at the McBain's. Even more crucially, his death was removed at the end. The last you saw of him and Harmonica was the two of them riding off together. This was the version released in the US and it wasn't a success. In most of Europe, a 165 minute version was released, and in Italy the 171 minute version the way Leone intended it to be. In France it was a huge success and Leone was proud of the fact that one cinema in Paris played it uninterrupted for four 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 Le bon, la brute et le truand (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.
Unlike the Dollars trilogy, which were all solely shot in Spain, Sergio Leone travelled to the U.S. to shoot some scenes in the iconic Monument Valley, one of John Ford's favorite locations, making it the first "spaghetti Western" to be shot in the U.S.
Luana Strode: The Indian woman who flees from the train station in the opening sequence. She was the wife of Woody Strode.