Exeter Chiefs boss Rob Baxter suggested a lack of experience for his side playing at Twickenham was a factor in losing to Quins.
The visitors were 19-3 down at half-time in their first match at the national stadium in London in front of a bumper crowd.
Having fallen behind to early tries from Nick Evans and Charlie Walker before Mike Brown added a third before the break, the Chiefs were left battling uphill and could only manage two penalties from Gareth Steenson.
The loss means Exeter slip to 6th and are now 19 points behind league leaders Saracens.
"In hindsight this result was probably to be expected a little bit because it was our first occasion at Twickenham," said Baxter.
"I'm not broken by losing to Harlequins away from home, I'm just disappointed we didn't show more of ourselves.
"We think we'll be involved in big games down the line so this was very important for us because if you want to win big games, you have to win at Twickenham.
"I was impressed by the intent and intensity that Quins brought to the game in the opening period. That knocked us out of our stride.
"The second half was better because we showed intent in the collisions and some attitude in what we did."