Super League leaders St Helens staged a fine second-half comeback, running in 26 points without reply to end Harlequins' play-off hopes.
Quins began brightly, with Rob Purdham and Scott Hill bagging early tries before Paul Clough pulled one back.
Julien Rinaldi restored Quins' 10-point advantage just before the break but Saints' second half reply was awesome.
Tries by James Graham, Jason Cayless, Willie Talau (2) and Ade Gardner made it 19 games without defeat for Saints.
Harlequins coach Brian McDermott:
"Defensively we cracked when they kept at us.There was always going to be a point where we would be under pressure, and we didn't cope.
"We got ourselves in a position where we were chasing a game we should not have been chasing.
"You have to score points when you are on top against St Helens, and that often means you will come up with mistakes."
St Helens coach Daniel Anderson:
"We are not always going to be perfect - and we were a little bit flat.
"We let them play football in the first half and we were lucky to only be 10 points down.
"But I do not think we could be accused of being flat in the second half, and the pressure told."
Harlequins: Melling, Sharp, Clubb, Howell, Sheriffe, Hill, Orr, Ward, Randall, Haggerty, Temata, Purdham, Paul. Replacements: Rinaldi, Heckenberg, McCarthy-Scarsbrook, Grayshon.
St Helens: Wellens, Gardner, Gidley, Talau, Meli, Pryce, Eastmond, Cayless, Cunningham, Graham, Gilmour, Wilkin, Flannery. Replacements: Hargreaves, Fozzard, Roby, Clough.
Referee: S Ganson (St Helens)
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