Portugal centre-back Pepe returned after a month out with a substitute appearance against Sevilla on Saturday and is likely to start against Sir Alex Ferguson's side.
Angel Di Maria (thigh) is ruled out for both legs but Jose Mourinho could have Xabi Alonso back after he returned to training this week.
Sir Alex Ferguson faced two fresh injury blows after beating Everton on Sunday, as Phil Jones (thigh) and Jonny Evans (knock) were forced off in the 2-0 win at Old Trafford.
Rio Ferdinand is likely to return to partner Nemanja Vidic at centre-back, while Robin van Persie should lead the visitors' attack with Wayne Rooney deployed in a deeper midfield role.
Real Madrid have won the European Cup on a record nine occasions.
Cristiano Ronaldo netted his 20th hat-trick for the Santiago Bernabeu side against Sevilla at the weekend, overtaking Paco Gento in the club's scoring charts.
The Portuguese has scored over 100 goals for both clubs. He has 183 for his current side and netted 118 goals in 292 appearances for Manchester United.
The last time the two sides met in the Champions League the tie ended 6-5 to the Spanish outfit, with Brazilian striker Ronaldo stealing the show with a hat trick at Old Trafford.
Jose Mourinho has never won a Champions League game at Old Trafford. Porto's progress was built on a 1-1 draw while Inter lost 2-0 at United in 2008-09.On the two occasions the Real Madrid boss has won the Champions League his side have knocked out English opposition in the last 16.All three of Van Persie’s (pictured) goals in the Champions League this season have come away from home.The Red Devils have conceded exactly three goals in three of their four trips to the Santiago Bernabeu.Manchester United have only won two of their 13 away Champions League games in Spain.