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Following the onscreen credits, voice-over narration, describing Macao as the "Monte Carlo of the Orient," is heard over footage of the island. According to RKO production files contained at the UCLA Arts-Special Collections Library, background shots were filmed in Macao and Hong Kong. In May 1948, Hollywood Reporter announced that Universal-International had purchased the screen rights to a story entitled "Macao," which was described as a "post-war story, localed off the China coast." It has not been determined if the Universal story is related to the RKO picture. RKO purchased Bob Williams' story in August 1949, according to a Hollywood Reporter item. Although the same item noted that Williams' story was "headed for early publication," no information about the story's publication has been found.
Production files and Hollywood Reporter news items add the following information about the picture: Sid Rogell was the film's original executive producer. Lisa Faraday and Joyce McKenzie tested for the role played by Gloria Grahame, which according to modern sources was originally conceived as a Eurasian. William Tallman tested for the role of "Halloran," according to production files. George Macready tested for a role, but was not in the final film. In early August 1950, actor Keye Luke was hired to create four murals for the film's casino scenes, and Ed Vorkapich, the son of montage editor Slavko Vorkapich, did sketches for director Josef von Sternberg. Location shooting took place in San Pedro and the Malibu pier.
Macao was von Sternberg's first credited feature release since the 1942 United Artists picture The Shanghai Gesture (see AFI Catalog of Feature Films, 1941-50). In 1950, Von Sternberg directed RKO's Jet Pilot but it was not released until 1957. According to modern sources, following two screenings of a rough cut of the film and a preview screening in Pasadena, Bischoff ordered extensive rewrites and retakes. Von Sternberg, who had a two-picture contract with RKO, declined to direct the retakes. Robert Stevenson directed retakes in February 1951 and Nicholas Ray directed retakes in July 1951, according to production files. The following writers were listed in production files as contributors to the revised script: Edward Chadosov, Norman Katkov, Walter Newman, George Bricker and Frank Moss. The extent of their contribution to the final film has not been determined, however. Producer Jerry Wald supervised retakes shot by Ray, according to production files. In July 1951, actor-director Mel Ferrer directed one day of retakes. Ray and Grahame, who married in 1948, separated during the retake shooting and later divorced.