Harlequins all but ended London Irish's hopes of progressing into the LV= Cup knockout stages thanks to a 16-13 win at the Madejski Stadium.
Teenage winger Sam Smith made it two tries from two senior starts as Quins ended their six-match losing run in Sunday's fixture.
Meanwhile, fly-half Nick Evans kicked eleven points as the visitors put themselves in the mix for a semi-final spot.
Smith, the 19-year-old academy player who marked his debut with a try against Newcastle in an LV=Cup win earlier this season, intercepted a pass and raced 80 metres for the crucial touchdown late in the first half.
The Exiles, now without a win from their last four matches, had more possession and territory than the visitors but lacked the clinical finishing to make it pay.
To add to their problems, fly-half Ryan Lamb had a miserable day with the boot, landing only one of three penalty shots and missing both conversions after centre Jonathan Joseph scored two second-half tries.
Harlequins, already without England elite squad members Ugo Monye, Danny Care, Nick Easter and Chris Robshaw, along with David Strettle on duty for the Saxons, had to make another change when skipper Will Skinner pulled out with a knee injury before the match. He was replaced by Neil McMillan.
Irish fielded an equally unfamiliar line-up as they were deprived of eight potential starters, including the England trio of scrum-half Paul Hodgson and brothers Delon and Steffon Armitage, by international calls, injuries and the suspension of Tonga number eight Chris Hala'ufia.
Evans kicked Quins into a third-minute lead when Irish were caught offside in front of their own posts but Lamb was denied an equaliser five minutes later when his penalty struck the post after a scrum infringement.
Former England star Mike Catt, the 38-year-old assistant coach making a rare appearance for the Exiles, showed his sharpness by making up ground to tackle Gonzalo Tiesi as the Argentina centre tried to run the ball out of defence.
But Quins went further ahead with a 19th-minute penalty from former All Black Evans after Irish killed the ball at a ruck.
Irish twice spurned kickable penalty opportunities in their search for a try but a lack of handling precision let them down both times.
Then stand-in skipper Peter Hewat, linking up from full-back, raced down the left touchline to cross but the touch judge spotted he had put a foot in touch as he evaded the Quins' cover.
But Irish, continuing to pressurise the visiting defence, were hit by a breakaway try when Hewat's pass, aimed for winger Topsy Ojo, was grabbed by Smith who showed a clean pair of heels to race from inside his own 22 to touch down between the posts, leaving Evans a simple conversion.
Quins had centre Jordan Turner-Hall yellow-carded for a blatant late challenge on Lamb, who had just kicked deep into their half, but had a let-off when the fly-half missed the resulting penalty from well within his range.
Down to fourteen men, Harlequins moved further ahead when Evans landed his third penalty from just inside the Irish half to give them a 16-0 lead before Lamb finally opened his account at the third attempt with an in-off-the-post penalty eight minutes into first-half injury time.
The home side cut the deficit to eight points when Ojo battled through two tackles to send Joseph in after 55 minutes and the young centre scored his second try in the final minute, but Lamb pulled both conversions wide.
For London Irish:
Tries: Joseph 2
Pen: Evans 3
London Irish:15 Peter Hewat (c), 14 Topsy Ojo, 13 Jonathan Joseph, 12 Mike Catt, 11 Sailosi Tagicakibau, 10 Ryan Lamb, 9 Peter Richards, 8 George Stowers 7 Richard Thorpe, 6 Kieran Roche, 5 Andy Perry, 4 Gary Johnson, 3 Paulica Ion, 2 James Buckland, 1 Dan Murphy,
Replacements:16 Danie Coetzee, 17 James Tideswell, 18 Max Lahiff, 19 Matt Garvey, 20 Jamie Gibson, 21 John Rudd, 22 Alfredo Lalanne, 23 Jamie Lennard
Harlequins:15 Mike Brown, 14 George Lowe, 13 Gonzalo Tiesi, 12 Jordan Turner-Hall, 11 Sam Smith, 10 Nick Evans, 9 Karl Dickson, 8 Tom Guest, 7 Will skinner (c), 6 Chris York, 5 Lewis Stevenson, 4 James Percival, 3 John Andress, 2 Matt Cairns, 1 Ceri Jones.
Replacements:16 Chris Brooker, 17 Aston Croall, 18 James Johnston, 19 Tomas Vallejos, 20 Neil McMillan, 21 Steve So'oialo, 22 Rory Clegg, 23 Josh Drauniniu
Referee: Martin Fox