Ronaldo netted 118 goals in 292 appearances for United before making the move to Madrid, where he has continued that sensational run of form, having already registered 183 goals for the capital outfit.
The omens look good for Madrid boss Jose Mourinho with the Portuguese knocking out English opposition in the last 16 on the two occasions that he has won the Champions League.
The last time the two sides met in the Champions League was in 2003, when Brazilian striker Ronaldo scored a sensational hat-trick at Old Trafford to send the Spanish outfit into the next round.
United, who have conceded three goals in three of their last four trips to the Bernabeu, have only won two of their 13 away Champions League matches in Spain, but will feel confident of taking an away goal into the second leg with Madrid's defence hit with injuries in recent weeks.
Madrid enter the match off the back of a 4-1 win over Sevilla at the weekend, but a disappointing league season to date has seen them sit third in the La Liga table, some 16 points behind Barcelona and four points adrift of second-placed Atletico Madrid.
Madrid welcomed Pepe back at the weekend following a month on the sidelines, with the Portuguese expected to partner Sergio Ramos in defence. Angel di Maria is missing with a thigh injury, but Xabi Alonso should return alongside Sami Khedira after the pair both sat out the win over Sevilla.
United boss Sir Alex Ferguson rested Rio Ferdinand at the weekend, with the experienced defender expected to come into the team alongside Nemanja Vidic in central defence. Michael Carrick will also start, while Danny Welbeck should be given the nod in a wider position in order to combat the pace of Madrid on the counter.
Real Madrid: DWDLW
Manchester United: DWWWW
Real Madrid: Lopez; Arbeloa, Pepe, Ramos, Coentrao; Khedira, Alonso; Benzema, Ozil, Ronaldo; Higuain
Manchester United: De Gea; Rafael, Ferdinand, Vidic, Evra; Carrick, Cleverley; Welbeck, Kagawa, Rooney; Van Persie
Sports Mole says: 2-2