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The following written foreword appears after the opening credits: "1950 was a Holy Year. Three million pilgrims from every part of the world thronged to Rome, the Eternal City. Our story is about two men who journeyed to Rome that year. One was Father John X. Halligan, a young priest from Coaltown, Pennsylvania, whose mission was a holy one; the other was Joe Brewster, late of Sing Sing, San Quentin, Joliet and Atlanta, whose mission was not so holy...If our story has a moral, it's a simple one: God May move in mysterious ways, but He gets there just the same."
According to a Hollywood Reporter news item, actor Douglas Fowley was under consideration for a role in the film. Although actors Harry Shannon, Walter Sande, Curtis Cooksey, David Fresco, Larry Olsen and Robin Camp are listed on the CBCS, neither they nor their roles were in the released film. According to a Hollywood Reporter news item, When in Rome was to have been Cooksey's motion picture debut. Much of the film was shot on location in Rome. Roman locations included The Spanish Steps, the Colosseum and the churchs of Santa Maria Maggiore, St. John Lateran and St. Paul Outside the Walls. According to an M-G-M production memo included in the AMPAS Library file on the film, some interior shots of St. Peter's Basilica were also made. For additional information on the 1950 Holy Year, please see the entries for Holy Year 1950 and The Holy Year at the Vatican in AFI Catalog of Feature Films, 1941-50.