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In 1888 London, Mr Slade (Jack Palance), a respected research pathologist at University Hospital, rents a bedroom and an unused attic in the home of Helen (Frances Bavier) and William (Rhys Williams) Harley at the same time that the Whitechapel district is on edge due to the murderous fiend dubbed Jack the Ripper. Mrs Harley soon begins to suspect that her lodger may actually be Jack the Ripper.

Yes. Man in the Attic is based on The Lodger, a 1913 novel by English author Marie Belloc Lowndes. It is the fourth of five movies based on The Lodger, preceded by Il pensionante (1927) (1927), The Lodger (1932) (aka The Phantom Fiend) (1932), (1932), and Il pensionante (1944) (1944) and followed by The Lodger - Il pensionante (2009) (2009). The novel was adapted for Man in the Attic by screenwriters Robert Presnell Jr. and Barré Lyndon (pseudonym of Alfred Edgar).

Whitechapel can be located on the given map just east of London's city center. At the time that Jack the Ripper was terrorizing London, the Whitechapel district, and some of the surrounding areas, collectively known as "the East End," were considered to be the most impoverished, crowded, and dangerous areas in all of London.

Following the cancan performance given by Lily Donner (Constance Smith), Slade goes back to her dressing room and expresses his dislike with the way the men in the audience look at her. He kisses her abruptly and begs her to come away with him, but Lily is not about to give up the stage. While she finishes dressing, Slade locks the door then pulls out a knife and holds it to her throat, accusing her of using her beauty to corrupt and degrade men...just like his mother. As a crowd begins to amass outside Lily's dressing room and people start banging on the door, Slade drops the knife and crawls out a window. He eludes the police and steals a carriage while Inspector Warwick (Byron Palmer) pursues. When Slade's carriage rounds a corner too quickly and he loses a wheel, he once again eludes the helpful police by telling them that he is a doctor and must hurry. He continues running on foot as Warwick catches up. When Warwick tells the police that he's chasing Jack the Ripper, they all run after him. Slade attempts to elude his pursuers by wading out into the river. Warwick dives in after him, but Slade has disappeared.