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Although characters in the film address Wayne Morris's character as Walter Garrett, the onscreen credits and reviews list his name as Walter Barnett. Similarly, although onscreen credits list Cliff Saum as "Detective Sergeant Moran," reviews credit Jack Mower with the role. According to news items in Hollywood Reporter, Boris Karloff was originally slated for the lead in the film, but when his work on Enemy Agent prevented him from appearing, Warners began negotiations with Bela Lugosi for the lead. James Stephenson was then assigned to the role, but when he left to appear in The Private Lives of Elizabeth and Essex, Humphrey Bogart stepped in. Another item in Hollywood Reporter adds that George Amy was originally scheduled to direct.
The Return of Dr. X marked the directorial debut of former actor, screen writer and dialogue director Vincent Sherman (1906-2006). Sherman went on to direct dozens of films for Warner Bros., among them Old Acquaintance (1943, ) and The Hasty Heart (1949, ), as well as many television programs for that studio and others until his retirement in the 1980s.