It makes for an uncomfortable reunion for both - with memories of Messi's Champions League-winning performance against United in 2011.
And Lionel Messi will still be there.
Juventus have been handed a date Ajax while Liverpool take on Porto, Tottenham Hotspur lock horns against Manchester City and Manchester United tackle Barcelona for a place in the semifinals. Barcelona are the only club remaining to have won the competition in the past 10 years.
The last time the Premier League had four teams in the quarter-finals, in 2008/09, Barcelona beat the Old Trafford side 2-0 in the final in Rome.
He admits that playing at home in the second leg could be an advantage, but he was quick to stress the way Manchester United defied the odds against Paris Saint-Germain the previous round. @ManUtd, " Pique wrote on Twitter. Ole [Gunnar Solskjaer] going back to the Camp Nou will be big for him.
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For the first time in 10 years, four Premier League teams have qualified for the last eight in Europe's elite club competition, and, with 50% of the quarter-finalists coming from the EPL, it is no surprise that two English teams will meet each other in the next round.
That pairing brought together the only two quarterfinalists who have never been European champion.
There is no seeding or country protection in the Champions League quarter-final or semi-final draw. "I think it's the best league in the world now, the Premier League".
However, Porto have the second leg at home and if they can avoid a heavy defeat at Anfield in the first game, they will fancy their chances of turning it around.
Memorable quarter-final matches include that sensational 7-1 triumph over Roma - they lost the first clash 2-1 - during which they romped into a 4-0 half-time lead.
And Juventus' meeting with Ajax will be a rematch of the 1996 Champions League final at Rome's Stadio OIimpico, a match that the Italians won via a penalty shootout.