Cristiano Ronaldo will return to Manchester United with nine-time winner Real Madrid in the Champions League round of 16 and Lionel Messi's Barcelona takes on AC Milan.
Bayern Munich, last season's beaten finalist, plays Arsenal and Juventus takes on surprise qualifier Celtic.
Big-spending Paris St-Germain will face Valencia.
But the fate of the two Spanish giants in yesterday's draw at UEFA headquarters in Nyon, Switzerland, attracted most interest and both were pitted against clubs with decades of European experience.
Real, the Spanish champion, has been disappointing in La Liga this season and it finished second in its Champions League group behind Borussia Dortmund. But Ronaldo will be desperate for Real to rise to the occasion against the club at which he won the European Cup in 2008 and developed into a world-class forward.
Real manager Jose Mourinho, once of Chelsea, will also come up against his old rival Alex Ferguson.
"I'm sure it's going to be a special game for him (Ronaldo)," said Emilio Butragueno, Real Madrid's director of institutional relations. "I think the fans will be very, very happy with this very attractive, thrilling tie. It will be a great experience for everybody."
Barcelona is 2-1 favorites to win the Champions League although it could hardly have picked a club with more success in Europe in seven-time winner AC Milan when the competition resumes in mid-February.
Messi has scored 90 goals in 2012 and has fired Barcelona to a nine-point lead in La Liga while Milan is 14 points adrift of Juventus in Serie A and finished second behind Malaga in its group.
Barcelona vice-president Josep Maria Bartomeu told Spanish broadcaster Canal Plus: "Milan are one of Europe's greats and a club that commands a huge amount of respect.
"They are not going well in their league right now but they have some excellent players. They are not currently at their best but football changes from one day to the next."
In the other ties, Galatasaray will play Schalke 04, Shakhtar Donetsk takes on Dortmund and Porto faces Malaga.
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