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According to a June 1950 Hollywood Reporter news item, Paramount bought the rights to William Inge's play for $100,000, plus a percentage of the profits. Both Sidney Blackmer and Shirley Booth, who created the roles of "'Doc'" and "Lola" on the stage, were considered for the film, according to the Hollywood Reporter item, but only Booth was cast. Come Back, Little Sheba marked the screen debuts of Booth and director Daniel Mann. According to an October 1951 Variety news item, producer Hal Wallis considered casting Bette Davis as Lola when Booth appeared unavailable because of Broadway commitments. Modern sources note that Davis turned down the role. Booth, who won a Tony for her Broadway portrayal of Lola, also won a Best Actress Academy Award and was named best actress of 1952 by the New York Critics Circle. In March 1952, according to a New York Times item, Booth signed a three-picture contract with Wallis. Booth, who was in her mid-forties when she made Come Back, Little Sheba, appeared in only four more pictures. Her last screen role was in Paramount's 1958 release Hot Spell . In the early 1960s, she starred in the popular television series Hazel.
According to modern sources, Burt Lancaster persuaded Wallis to cast him as Doc, even though, at age thirty-eight, he was too young for the part. In his autobiography, Wallis commented that in order to make the trim and muscular Lancaster appear older, his baggy, shapeless costume was padded at the waist and he was instructed to stoop, hollow his chest and shuffle his feet. Critics praised Lancaster's performance. The Hollywood Reporter reviewer commented that it was a "complete switch from anything he has ever done and easily the outstanding effort of his career," while the Variety critic declared that the actor had "brought an unsupected talent" to the role.
The following actors were listed by the CBCS, but their roles were not included in the final film: Peter Leeds (Milkman), Anthony Jochim (Mr. Cruthers), Henry Blair (Western Union boy) and Beverly Mook (Judy Coffman). According to a February 1952 New York Herald Tribune article, scenes were added for the screen adaptation, including the sequence at the Alcoholics Anonymous meeting. Although the article states that scenes of Doc at work would be added, the final film does not include any office sequences. Hollywood Reporter news items add Mary Murphy and Patricia Christie to the cast, but their appearance in the final film has not been confirmed. Another Hollywood Reporter news item mentioned that Vince Edwards was being tested for a role, but he was not in the fil, Reviews and the CBCS list Terry Moore's character as "Marie Loring," but she is called "Marie Buckholder" in the picture. According to modern sources, location filming took place near the University of Southern California, in Los Angeles.
In addition to Booth's Oscar, the film was nominated for Best Supporting Actress (Terry Moore) and Best Film Editing Academy Awards. Modern sources note that the picture earned 3.5 million dollars at the box office and was the number thirteen money-maker of 1953. On December 31, 1977, the NBC network, in association with Great Britain's Granada Television, broadcast a televised version of Inge's play, starring and produced by Laurence Olivier and co-starring Joanne Woodward.