Saracens slumped to their first defeat in six months after Harlequins stunned the double winners 17-10 in a victory they will hope can ignite their Aviva Premiership campaign.
Leicester were the last side to inflict a loss on the domestic and European champions, triumphing 21-13 at Welford Road on March 20, but Quins' success at Twickenham Stoop was against a side armed with their England internationals.
Two defeats and a narrow win over Bristol had given John Kingston's reign as director of rugby a disappointing start, but a victory founded on an unyielding defence and tries born out of both opportunism and skill has propelled them up the table.
Tim Visser and Charlie Walker crossed in the first half, which they finished 17-0 ahead, before Saracens launched a fightback that gained momentum with Richard Wigglesworth's try before ultimately falling short.
Alex Lozowski has been a high-quality deputy for Owen Farrell, but Saracens missed the control and accuracy from the kicking tee of their England fly-half, who has yet to play this season due to a hip problem.
And only the club will know how much of a distraction Chris Ashton's 13-week ban for biting has been in the build up to one of the Premiership's feistier encounters.
Yet Quins could also point to a cruel 24 hours on the injury front with the news that Jack Clifford had been ruled out until December with an ankle issue followed by the loss of three more of their England contingent.
Marland Yarde was withdrawn from the starting XV shortly before kick-off due to a throat infection and Joe Marler's afternoon was over just seconds into the London derby after being accidentally knocked unconscious by Billy Vunipola's hip.
To compound their misfortune captain Danny Care limped off shortly after half-time clutching his ribs, but the setbacks were unable to deter the 2012 champions as they repeated January's triumph over their capital rivals at Twickenham Stoop.
The loss of Marler inside the opening seconds was brushed aside as Quins raced into a 10-0 lead through an intercept try by Visser, who picked off Lozowski's loose pass, and the kicking of Tim Swiel.
Saracens sought to stamp their authority on the match and enjoyed some success as they rolled downfield, but time and again they made uncharacteristic errors and all momentum was lost.
Feverish work at the breakdown helped Quins win a penalty and they then pursued the line-out drive, assisted by Jim Hamilton repeatedly pulling down the maul.
Referee David Grashoff played advantage, ready to award a fourth penalty in succession but the hosts spied their chance with a long pass from Swiel setting the backline moving.
At fast pace the ball was spun right where the onrushing Mike Brown drew the last defender and sent Walker racing over.
Swiel added the conversion and the lead had been stretched to a scarcely believable 17-0, although Brown's unhurried approach to dealing with the ball by his corner flag caused mild panic.
A try-saving enveloping tackle by Matt Hopper on Marcelo Bosch was the highlight of the last 10 minutes of the first half, most of which Quins spent camped on their goalline defiantly repelling a series of attacks.
Their defence was breached moments after the interval, however, when Mike Ellery weaved into space and chipped ahead, gathering his kick via a kind bounce before feeding Wigglesworth to score.
Both fly-halves struck the right post with penalty attempts and then Lozowski missed again as Saracens lamented the loss of the metronomic Farrell, enabling Quins to celebrate taking a prized scalp.