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The working titles of this film were Postal Inspector, United States Mail and Dead Letter. The order of the onscreen end credits differs slightly from that of the opening credits. The film opens with a voice-over narrator describing the workings of the U.S. Post Office and the job of postal inspector, "the nation's oldest police force." Various post offices, including the main office in Washington, D.C., are seen. Although the film did not open in the U.S. until May 1951, it was reviewed in the British Monthly Film Bulletin in April 1950 and opened in London shortly thereafter. According to a July 1948 Variety news item, Endre Bohem was first slated to produce the picture, and writers Ardel Wray and Robert L. Richards were assigned to the script. The contribution, if any, of Wray and Richards to the final film has not been determined. Although a January 1947 Variety item announced that Eagle Lion had purchased a screen story by Henry Sucher entitled "Postal Inspector," that story does not appear to have any connection to the Paramount property. According to a July 1949 Los Angeles Daily News news item, Appointment with Danger was based on a series of "true incidents from government files" and marked the first time that the Post Office Department had given its "complete co-operation" to a picture. Harold Ambrose, special assistant to the U.S. Postmaster, was reportedly sent to Hollywood to discuss the project.
In March 1949, Hollywood Reporter announced that William Keighley was directing the picture. Paramount publicity material, contained in the film's file at the AMPAS Library, announced that "radio personality" Blossom Plumb was to make her screen debut in the picture, but her appearance in the final film has not been confirmed. Stacy Harris, a regular on the radio series This Is Your F.B.I., made his screen acting debut in Appointment with Danger. By the time of the film's release, Jack Webb, who plays the homicidal "Joe Regas," was starring in the popular police radio series Dragnet. The series began on television in 1952, and in 1967, Henry Morgan, who plays Webb's partner-in-crime in Appointment with Danger, became Webb's co-star in a new television version of Dragnet. As noted in news items and studio publicity, two weeks of location filming took place in Chicago, IL, and Gary, La Porte and Fort Wayne, IN. On January 19, 1953, William Holden and Coleen Gray appeared in a Lux Radio Theatre version of the story.