Mankiewicz and producer Darryl F. Zanuck initially considered Susan Hayward for the role of Margo, but decided she was not old enough. Claudette Colbert was cast as Margo in Feb 1950, but was forced to withdraw from the production when she injured her back. Modern sources provide the following information: Zanuck then suggested casting Marlene Dietrich as Margo, Jeanne Crain as Eve, John Garfield as Bill Sampson and José Ferrer as Addison DeWitt.

Mankiewicz sought noted stage actress Gertrude Lawrence for the role of Margo, but her attorney, Fanny Holtzman, insisted that the screenplay be changed so that Lawrence did not smoke or drink in the picture, and would sing a torch song about Bill in the party scene. Zanuck also sought Ingrid Bergman to replace Colbert, but the actress refused to leave Italy, were she was living, for the production. A 16 May 1950 HR news item adds Gertrude Astor and Franklyn Farnum to the cast, but their appearance in the final film has not been confirmed.