Sitiveni Sivivatu's late try halted Harlequins' Heineken Cup recovery in its tracks as Clermont Auvergne clinched a 16-13 victory at the Stoop.
Clermont fly-half Brock James failed to convert the Kiwi flyer's 72nd-minute score but the Australian landed a late penalty to seal victory for the French giants and end Quins' hopes of reaching the knock-out stages.
Danny Care's moment of magic in the first half had inspired Quins to a 13-3 lead at the break, at that stage sustaining the Londoners' hopes of becoming the first side to lose their first two matches and reach the quarter-finals.
But scores from Napolioni Nalaga, who capitalised on a costly error from England full-back Mike Brown, and Sivivatu sealed Harlequins' fate.
Clermont began ominously and moved ahead after three minutes when Harlequins were penalised at the ruck and James made no mistake from the tee in front of the posts.
Slowly, Quins grew into the game and had the opportunity to level after winning a penalty from a line-out when Nathan Hines came around the side of a maul, but Nick Evans pushed his attempt from the left past the far post.
Quins were nearly made to rue that miss as twice in quick succession Clermont created glorious chances for the first try of the match, only for handling to let them down.
Firstly, James chipped an inch-perfect kick to the left and found Nalaga in space, only for the Fijian to drop the ball, while just a minute later it was number eight Fritz Lee who knocked on with the try-line beckoning.
And it was not long before Harlequins made them pay with the first try thanks to Care's perfectly-executed piece of improvisation.
The scrum-half started the move, taking a quick penalty inside his own half, and spread the ball wide to Ugo Monye on the left, who in turn off-loaded to Chris Robshaw.
The England captain kicked ahead and the chasing Care gathered the ball and produced a magical back-of-the-hand pass into the hands of the onrushing Matt Hopper, who had the simplest of finishes.
Evans was on target with the conversion before landing a penalty from 45 metres to give Quins a 10-3 lead after half an hour.
The momentum was firmly with the hosts and moments later Evans found a gap in the Clermont defence and darted through it. And while he could not find Charlie Walker in support, the visitors were penalised for offside and Kiwi fly-half Evans extended Harlequins' lead.
Clermont reduced the gap to five points six minutes into the second half when Brown was deceived by the bounce of the ball on his own 22 and slipped, allowing Fijian winger Nalaga to profit.
The impressive Care then had to be helped from the field with an ankle injury, a concern for England head coach Stuart Lancaster ahead of the Six Nations, with Karl Dickson replacing him.
Clermont were knocking firmly on the door but Quins' defence continued to hold and with 10 minutes remaining Evans had the chance to put the home side eight points clear, and crucially put the visitors outside of a losing bonus point, but he pulled his kick from 35 metres wide.
Clermont made Evans pay for his miss immediately and the ball was spread wide to Sivivatu, who went over in the corner.
James then landed a penalty from 35 yards to ensure there was not another famous victory for Quins against French opposition as Clermont became the first side to qualify for the quarter-finals.