It was at Barcelona's stadium that Ole Gunnar Solskjaer enjoyed his finest moment as a Manchester United player, scoring a last-gasp winner to seal the Champions League title - and the treble - for his side 20 years ago.
The Norwegian's finest moment as a manager so far came in the last round of this season's competition, meanwhile, as United produced a miraculous comeback to beat PSG on away goals.
An injury and suspension-ravaged side became the first team in Champions League history to overturn a 2-0 home first-leg defeat and still progress, winning 3-1 at the Parc des Princes to book their place in the quarter-finals for the first time since 2013-14.
United face similarly large odds to progress from this tie, and they may take warning from their Spanish opponents, who also produced a historic comeback against PSG at the same stage of the 2016-17 campaign only to go on and lose in the following round.
A club the size of United should be gracing these stages on a regular basis, but to have made it this far in such a turbulent campaign should be regarded as a major achievement and anything beyond the quarter-finals will surely be just a bonus.
However, there will be plenty of fans who believe they can upset the odds again against Barcelona, having already won away at Juventus and PSG in this season's competition, proving that they are capable of beating Europe's heavyweights in their own backyard.
It is actually their home form which has let them down in Europe this term; United have won and scored just once in front of their own fans - a last-gasp triumph over Young Boys in the group stages - and including last season they have now lost three of their last five home Champions League outings.
Home and away United have been beaten three times already in this season's competition, but it has been a mercurial European campaign and they have shown that they can be very dangerous on their day too.
The Solskjaer honeymoon period does seem to be coming to an end, though, with United losing three of their four games since that unforgettable night in Paris - including away to Wolverhampton Wanderers last time out.
The Red Devils are subsequently three points adrift of the top four domestically with only six games of their season remaining - including matches against Manchester City and Chelsea.
United have at least had eight days to rest ahead of Barcelona's visit, and the fresh legs could help them to improve a poor recent record against Spanish opposition which has seen them win just two of their last 15 such games - and none of the last six.
Recent Champions League form: LWWLLW
Recent form (all competitions): WWLLWL
For all of Barcelona's domestic success in recent years, there has been a feeling of underachievement due to their lack of silverware on the European stage.
The five-time champions have fallen at this quarter-final stage in each of the past three seasons since last lifting the trophy in 2015 - a failure made even more difficult to stomach by bitter rivals Real Madrid then going on to be crowned Kings of Europe on each occasion.
It is nonetheless an unprecedented 12th successive Champions League quarter-final for the Spanish champions, though, and they remain firmly on course for a famous treble this season.
Having already reached yet another Copa del Rey final, Barca effectively sealed the La Liga title at the weekend with a hard-fought 2-0 win over 10-man Atletico Madrid at Camp Nou, a result which took them 11 points clear at the top with seven games remaining.
Luis Suarez and Lionel Messi were the heroes on that occasion - as they were four days earlier when Ernesto Valverde's side rescued a remarkable 4-4 draw with Villarreal to ensure what is now a 16-match unbeaten streak remained intact ahead of this trip to Old Trafford.
The topsy-turvy eight-goal thriller was the only match in Barcelona's last nine that they have failed to win - a run which includes the 5-1 triumph over Lyon at Camp Nou which ensured their place in the hat for the quarter-finals.
It is away from home where the issues have come for Barcelona in the Champions League, though, and remarkably you have to go back to the round-of-16 match against Arsenal in 2016 for the last time La Blaugrana won a European knockout game on the road.
Indeed, Barca have only scored one goal in the six such matches since then too, and the memories of their 3-0 defeat to Roma at this stage last season - after a 4-1 win in the home first leg - will still haunt many of Valverde's squad.
The Spanish giants have lost their last three away quarter-final legs without scoring a single goal, but they have already won in England this season courtesy of their 4-2 triumph over Tottenham Hotspur in the group stages.
That was a ninth win in their last 13 European games against English clubs - with just one defeat in that time - and their loss to Chelsea in the 2012 semi-finals is their only one in their last eight two-legged ties against Premier League teams.
It is also worth remembering that, for all of their troubles at this stage of the competition in recent years, Barcelona have also only lost one of their last 19 Champions League matches.
Recent Champions League form: WDWDDW
Recent form (all competitions): WWWWDW
United were able to welcome Marcus Rashford and Alexis Sanchez back to training on Tuesday, and the former could be set to return to the starting XI too after missing the Wolves game with an ankle problem.
Matic was an unused sub for that match but now faces a race to be fit in time for Wednesday, with Scott McTominay on standby to start again if the Serbian falls short.
Barcelona, meanwhile, are hopeful of welcoming Ousmane Dembele back into their squad, with the winger having been sidelined since the last-16 tie with Lyon.
Dembele's return could be the only change from the weekend win over Atletico, though, with Philippe Coutinho the most likely to sit out should the Frenchman be deemed fit enough to start.
Messi - scorer in two Champions League finals between these teams - remains their main dangerman with 26 goals in his last 22 games for the club, and he sits level with Robert Lewandowski as the competition's top-scorer this season.
The Argentine has 22 goals in 30 previous games against English opposition too - more than he has managed against teams from any country other than Spain.
It will be a particularly special occasion for Gerard Pique as he makes his first return to Old Trafford since leaving United in 2008, while Ivan Rakitic is expected to make his 100th appearance in UEFA club competitions.
Man Utd possible starting lineup:
De Gea; Young, Smalling, Lindelof, Shaw; McTominay, Matic, Pogba; Lingard, Lukaku, Rashford
Barcelona possible starting lineup:
Ter Stegen; Roberto, Pique, Lenglet, Alba; Rakitic, Busquets, Arthur; Messi, Suarez, Coutinho
Head To Head
This will be the 12th meeting between these two sides, and Barcelona narrowly edge the head-to-head record with four wins to United's three in that time.
The last two clashes have both come on the biggest stage of all, with Barcelona beating United in the Champions League finals of both 2009 and 2011.
United have won both previous two-legged contests between these two sides, though, most recently when Paul Scholes's last-gasp strike sent them through to the 2008 final with the Red Devils' only triumph in eight previous Champions League games against Barca.
The Spanish giants are responsible for United's heaviest ever Champions League defeat - running out 4-0 winners in the 1994-95 group stages - although United have never lost at home to Barcelona (W2 D2).
We say: Man Utd 1-2 Barcelona
United do not come into this match in particularly good form and, while their most recent defeats have come away from home, it is at Old Trafford that they have struggled in Europe this term. Barcelona, by contrast, are in fine form and we are backing them to come away with a valuable away victory on Wednesday.