The Quins secured their bonus point with a last-minute try from Mike Brown, which man of the match Nick Evans converted for a match tally of 17 points.
The final scoreline was harsh on the Sharks who competed throughout but the Quins were always the more creative side.
Harlequins made a blistering start. They immediately gained possession from the kick-off to produce a two-minute period of pressure, which ended with Ugo Monye being driven over for a try which Nick Evans converted.
Minutes later, Sale had their first chance for points but Danny Cipriani badly missed a 35-metre penalty attempt from almost straight in front of the posts.
When Mike Brown was penalised at a ruck 40 metres out, Cipriani was given another penalty chance and this time he made no mistake with his kick.
The opening quarter was frenetic with the hosts trying to exploit the ideal playing conditions by running the ball at every opportunity. However careless handling cost them at crucial stages, allowing the visitors to remain in touch.
Sale had another chance to reduce the deficit but Cipriani was narrowly wide with a penalty attempt from just inside his own half.
Against the run of play the visitors took the lead after 20 minutes.
A clever pass from Cipriani allowed Sam Tuitupou to make a big hole in the home defence. The ball was recycled and Richie Vernon raced beyond the cover defence for a try. Cipriani's conversion from the touchline rebounded back off the post.
The Sharks became more competitive but it was Harlequins who regained the lead six minutes before the interval with another excellent try.
They won quick ball from a lineout 40 metres out, Danny Care's swift pass sent Nick Evans sailing though a huge gap in the visitors' defence and Jordan Turner-Hall was on hand to collect the scoring pass.
Evans converted to give the Quins a deserved 14-8 interval lead.
An excellent take-and-kick from Evans put Harlequins on the attack early in the second half and when Sale were penalised, the outside-half kicked a 30-metre penalty to extend his side's advantage.
Evans then saved the home side with a try-line tackle before kicking another penalty after the Sale pack infringed when under severe pressure at the set scrum close to their line.
Sale responded with a second penalty from Cipriani to be trailing 20-11 at the end of the third quarter.
Strong bursts from replacement Maurie Fa'asavalu and Monye gained the hosts a position in the Sharks 22 and once again Sale were penalised to allow Evans to kick his third penalty.
Cipriani gave Sale a glimmer of hope with his third penalty with 10 minutes remaining but that was his last slice of action as he was replaced by Nick Macleod.
With six minutes to go Harlequins effectively sealed their victory.
Mike Brown produced one of his trademark elusive bursts to set up the platform from which George Robson crashed over from short range for their third try which Evans converted.
Brown's late effort put gloss on the win.
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