Liverpool were brought down to earth in the Europa League on Thursday after losing 1-0 at Sporting Braga in the last 16, while big-spending Manchester City crashed 2-0 at Dynamo Kiev.
Liverpool rejuvenated under interim coach Kenny Dalglish and 3-1 victors over arch-rivals Manchester United on Sunday, will have to turn their tie around in the March 17 return leg if they are to reach the quarterfinals.
Braga took the lead in the 18th minute in Portugal, with Alan guiding an emphatic penalty into the bottom-left corner after Mossoro had been sent sprawling by Sotiris Kyrgiakos.
Full-back Silvio came within inches of doubling the hosts' advantage 20 minutes later but his magnificent left-foot half-volley from 25 yards crashed back into play off the crossbar.
With Liverpool toiling, Dalglish introduced striker Andy Carroll for his European debut just before the hour and the burly former Newcastle man had an immediate impact.
A Carroll knock-down obliged Braga goalkeeper Artur to save at Dirk Kuyt's feet before Carroll saw a deflected left-foot shot fall narrowly wide of the left-hand post.
Kuyt then drew a sharp stop from Artur with an instinctive half-volley from the edge of the box but Braga, Champions League debutants earlier this season, withstood the pressure to claim a memorable victory.
"The way we started the game, the first 35 minutes, we were terrible," said Dalglish.
"To the boys' credit, they picked themselves up a bit in the second half. I think at 1-0 you have got a chance."
City completed an underwhelming evening for the English sides as they went down 2-0 amid freezing conditions in the Ukrainian capital.
Former AC Milan and Chelsea striker Andriy Shevchenko gave the hosts a 25th-minute lead when he diverted Andriy Yarmolenko's left-wing cross past Joe Hart to claim his 67th goal in European competition.
City introduced Carlos Tevez from the bench in the second half but to no avail, as Oleh Gusev doubled Dynamo's advantage by controlling a clearance on his chest and volleying home.
"The match was good, we played well, but we made two mistakes for the goals and you can't make mistakes in games like this," said City coach Roberto Mancini.
Portuguese champions Benfica had to dig deep as they fought back from a goal down to beat Paris Saint-Germain 2-1 at the Estadio da Luz.
Peguy Luyindula put PSG ahead before Mevlut Erding struck the post for the French side, but Maxi Pereira slammed in an equaliser shortly before half-time and Franco Jara lashed home a low shot to claim victory in the 81st minute.
Dutch champions FC Twente took a sizeable step towards the last eight after Luuk de Jong claimed a brace in a 3-0 win at home to 2008 champions Zenit Saint-Petersburg.
Spartak Moscow struck a blow for their country in the night's other Dutch-Russian encounter, however, by prevailing 1-0 at Ajax.
Earlier, Villarreal asserted control of their tie against Bayer Leverkusen as a neat individual goal in the fourth minute of injury time from Nilmar earned them a last-gasp 3-2 victory in the away leg.
Michal Kadlec's fine 30-yard opener for the hosts was cancelled out by Giuseppe Rossi before Nilmar put Villarreal ahead in the 70th minute.
Gonzalo Castro drew Leverkusen level immediately but Brazil international Nilmar had the final say in added time to put his team firmly in the driving seat.
Elsewhere, a powerful 70th-minute effort by Colombian midfielder Fredy Guarin gave Portuguese league leaders Porto a 1-0 win at CSKA Moscow, while Scottish champions Rangers' visit to PSV Eindhoven finished goalless.