Unsettled by the extra bounce of the Perth pitch, the Sixers were dismissed for 97 in reply to the Scorchers’ 4-183 from their 20 overs on Wednesday night.
Jack Edwards (44 from 38 balls) managed the Sixers’ only substantial score.
Despite the loss the Sixers remain on top of the BBL table with 21 points, two ahead of cross-town rivals Sydney Thunder.
The Sixers’ next match is against the Brisbane Heat at the Gold Coast’s Metricon Stadium on Sunday.
It was the he first of four home matches for the Scorchers at Perth Stadium this season.
They were propelled to a competitive total by Mitch Marsh, who made an unbeaten 57 from just 27 balls with seven fours and two sixes. Opening bowler Jhye Richardson claimed 3-15 from his four overs and AJ Tye 4-20.
Pitches in Perth have a well-deserved reputation for aiding fast bowlers on hard and bouncy surfaces but the Sixers defied history with their spinners.
Veteran Steve O’Keefe (2/33) and tyro Lloyd Pope (2/13) claimed all four Scorchers wickets to fall.
O’Keefe was successful opening the bowling with his left arm finger spin, claiming 1/14 from his first three overs.
Pope was then the X-Factor replacement for the Sixers when their leading wicket-taker this season, Ben Dwarshuis, was subbed out with a minor groin strain which may keep him out of the next game.
O’Keefe claimed the first wicket of the match when English important Liam Livingstone (16 from 13 balls) holed out to deep mid-wicket.
The Scorchers were 1/71 after 10 overs when Lloyd was subbed in with New Zealander Colin Munro begin to unleash. He clubbed Lloyd’s first ball for six but two balls later was well caught by Jackson Bird at square leg. Munro made 50 from 34 balls.
England white ball opener Jason Roy again struggled against spin, with Pope conceding just three singles from his second over before Roy (27 in 31 balls) holed out to deep square leg.