Cristiano Ronaldo will return to Manchester United with nine-times winners Real Madrid in the Champions League round of 16 and Lionel Messi's Barcelona take on AC Milan.
Bayern Munich, last season's beaten finalists, play Arsenal and Juventus take on surprise qualifiers Celtic.
Big-spending Paris St Germain will face Valencia.
But the fate of the two Spanish giants in Thursday's draw at UEFA headquarters attracted most interest and both were pitted against clubs with decades of European experience.Real, the Spanish champions, have been disappointing in La Liga this season and they finished second in their 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 are now 2-1 favourites to win the Champions League although they could hardly have picked a club with more experience of success in Europe in seven-times winners 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 are 14 points adrift of Juventus in Serie A and finished second behind Malaga in their 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 take on Dortmund and Porto face Malaga.Champions League last 16 draw:
Galatasaray (TUR) v Schalke 04 (GER)
Celtic (SCO) v Juventus (ITA)
Arsenal (ENG) v Bayern Munich (GER)
Shakhtar Donetsk (UKR) v Borussia Dortmund (GER)
AC Milan (ITA) v Barcelona (ESP)
Real Madrid (ESP) v Manchester United (ENG)
Valencia (ESP) v Paris Saint-Germain (FRA)
FC Porto (POR) v Malaga (ESP).
Photograph: Paolo Bruno/Getty Images