It's surely the highlight of the round, and this is a fixture packed with great matchups, context, emotion, and best of all, it's almost impossible to pick a winner.
Manchester United will play Real Madrid for the first time since that game in 2003, when a Ronaldo hat-trick earned a standing ovation from the home crowd at Old Trafford as it sent the hosts out despite a 4-3 victory.
That game is dripping with historical significance because it provoked Alex Ferguson to finally destroy that great Manchester United side, but this one will be important for another matter: Cristiano Ronaldo.
The Portuguese winger has not played against United since making his world-record transfer to the Spanish giants, and you can bet that no matter what else happens, it will all be about him. Yet aside from that, this is a well-balanced tie. Real have the better team on paper, but in big, two-legged encounters like these, have a recent history of playing well below themselves while United, by contrast, tend to bring their A-game. This also gives us a managerial match-up of Sir Alex Ferguson vs. Jose Mourinho - the last time, Ferguson prevailed by defeating Mourinho's Internazionale on the way to the final. This time, things could be different.
Cristiano Ronaldo. Obviously. The winger has constantly spoke highly of both the club and Ferguson since he left, while songs are still sung about him at pretty much every United away game. It'll be an emotional encounter for everyone, but also a pretty terrifying one if you're in a red shirt. Ronaldo is the match-winner to end all match-winners - with him in the game, United will know they are never entirely safe.
Matchups to watch
Cristiano Ronaldo vs. Patrice Evra - If Mourinho has any sense - and he does, he's Jose Mourinho, for christ's sake - then he'll deploy Ronaldo to threaten United's vulnerable left flank. Patrice Evra's form has declined alarmingly in recent seasons, particularly the defensive side of his game, so in theory Ronaldo will be able to have his wicked way with him throughout the whole 180 minutes plus. Ferguson's not that daft though, so you'd imagine he'll have a plan to aid the Frenchman. What it could be will be open to question.
The entire Real Madrid team vs. David de Gea - The young Spanish goalkeeper has been linked with a move to Real Madrid already, and with the form United's defence are in, he'll have to be at his best to keep the scores low. Fortunately, the keeper is both well-accustomed and well-equipped to desperate strings of shot-stopping in lieu of a decent defence, and it's pretty much nailed on that he'll have to do the same here.
Shinji Kagawa\Wayne Rooney vs. Sami Khedira\Pepe - For all United's 'midfield problems', at the sharp end of the middle of the pitch, they're remarkably strong. They can attack the hole with Wayne Rooney in his position there, and Shinji Kagawa is almost certain to feature at some point too. Both are energetic, hard-working players who can't be left alone, so it's unlikely Madrid will be able to just put Xabi Alonso there. They'll need better cover, and it'll come from Pepe and Khedira, whether they're stepping up from defence or playing there. Whether they have the discipline to match Rooney's physicality and deal with Kagawa's trickery will be intriguing.
A penalty shootout, because it's almost impossible to call. Real Madrid are the better team, but they have a history of not living up to that in this competition, while United tend to play above themselves in these sorts of games. Having said that, it's often down to Ferguson picking a better team than his counterpart, but he's made some odd choices lately and he's up against Jose Mourinho, who is no idiot.
Real Madrid are in poor form in La Liga, while United are playing well at the moment and historically tend to be playing at their peak around the time this tie will take place. On the other hand, Xabi Alonso, Sami Khedira, Luka Modric and Mesut Ozil will be lining up against Michael Carrick, Tom Cleverley and Anderson. There's an equal argument to be made for both sides.