Saul Niguez scored the only goal as Atletico Madrid inflicted a 1-0 defeat on Champions League holders Liverpool on their return to the Wanda Metropolitano.
Spain striker Saul fired home after just four minutes to give Atletico the advantage after the first leg of their last-16 tie against the 2019 champions.
Liverpool pushed and probed thereafter, but failed to muster a single shot on target as Atletico retreated into a defensive rearguard action to thwart the Premier League leaders.
Despite having plenty of the ball, Jurgen Klopp's men could not find a way through, making for an unhappy return to the venue where they won last year's final.
Liverpool were left to rue a very sloppy start that saw Saul pounce in the opening minutes.
The visitors had already been let off when a dangerous cross from the impressive Renan Lodi whistled just over Alvaro Morata's head and was put behind for a corner.
There was no respite from the resulting set-piece as Koke's delivery struck Fabinho and found its way to Saul, who slid the ball past Alisson Becker from close range.
Liverpool had another scare soon after when Angel Correa got behind their shaky defence, but his ball across goal found no one and thereafter Klopp's side began to gain a grip.
They met with continual frustration, however, as Atletico sat back to absorb pressure and waste time whenever they could. For all Liverpool's possession, the hosts were almost impossible to break down.
Mohamed Salah did put the ball in the net after a poor clearance from Jan Oblak, but it was disallowed for offside against Roberto Firmino and it was almost half an hour before Liverpool had a serious shot.
That came from Andy Robertson and flew wide before Fabinho also missed the target. Good work by Firmino and Sadio Mane created an opportunity for Salah but his shot was deflected over.
Yet Atletico would not let Liverpool create any rhythm.
They pushed again after the break and Salah should have done better when he headed wide at the back post from a Joe Gomez cross.
Time after time Liverpool were repelled in or around the Atletico box and their frustration increased with every injury or delayed throw-in.
For all that, Liverpool were almost caught out again when Lodi got behind the defence and crossed for former Chelsea striker Morata, but Trent Alexander-Arnold got back to clear. Lodi also flashed a shot wide from distance.
Jordan Henderson tried to pick up the pace but dragged a shot wide and saw another driving run come to nothing. The Reds captain left the field 10 minutes from time clutching his leg.
There was to be no way through and Liverpool, who have never lost a two-legged European tie under Klopp, were left with it all to do in the return leg at Anfield in three weeks.