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Tom Brady gave the home side a good start, diving into the corner for the opening try of the match after just five minutes.
Harlequins continued to dominate at the start of the second half as Sam Smith went over following a sprint down the left wing.
Maurie Fa'asavalu ended any hopes of a Sale comeback inside the last 10 minutes, adding the visitors' fourth try of the night, before the hosts were awarded a penalty try late on.
The result allows Harlequins to leapfrog the Sharks to move up to fifth in the table.