The world's most expensive player has won over the Bernabeu faithful with some breathtaking performances and will have the perfect opportunity to showcase his talents against the Premier League leaders.
The managerial battle between Real's Jose Mourinho and United's Alex Ferguson is another fascinating aspect of the tie but Ronaldo's bid to destroy his old team mates should take centre stage as two of the world's biggest clubs lock horns.
Seen as a more mature and less selfish player, Ronaldo has a chance to live up to comparisons with former Real great Alfredo Di Stefano as he faces United for the first time since the club paid 94 million euros ($126 million) to lure him to Spain in 2009.
Now 28, he made his name in England after joining from Sporting as an 18-year-old in 2003 and went on to win the World Player of the Year award five years later.
He has been in scintillating form since the turn of the year and warmed up for the United game with a hat-trick in a 4-1 destruction of Sevilla, earning a rousing ovation from the home faithful when he was substituted late on.
It is a significant turnaround from a difficult patch earlier in the season when he raised eyebrows and prompted talk of an exit from the club by telling reporters he was unhappy "for professional reasons".
Ronaldo said it was not about money and he and the club now appear to have put it all behind them so he can focus on helping Real secure the 10th European crown that has eluded them since their last triumph in 2002.
"The Champions League is very special at Madrid because we want to win a 10th European title," Ronaldo said in an interview with British daily The Sun. "For me it is the pinnacle.
"There are so many memorable matches that remain in the minds of the players and the fans. I want to make my contribution, I want to leave my mark."
Ronaldo spent six seasons with United and scored 118 goals in 292 games.
At Real he has netted 182 in 179 matches, a far higher goals-per-game ratio than Di Stefano's 308 in 396 appearances in the 1950s and 60s when he helped the club to five successive European titles.
Wednesday's match also renews the intriguing rivalry between Mourinho and Ferguson who have struck up a friendship over the years and are known to enjoy a glass of wine together.
"I feel privileged to be his friend because he is one of the most important people in the football world and, much more importantly, because he is a good person," Mourinho said after watching United beat Everton 2-0 at Old Trafford on Sunday.
"Madrid-United is the match that everyone wants to see. The world won't be watching any other Champions League games so I hope we can give the world what they expect."
Mourinho has faced United twice at this stage of the Champions League, starting with Porto's success on the way to winning the trophy in 2004.
As Inter Milan coach, the Portuguese lost to United in the last 16 five years later but during three years in London as Chelsea manager he suffered only one reverse to the Manchester club, winning five games and drawing four.
History favours Real. They have won three of their four previous European ties against United - in the semi-finals in 1956-57 and the quarter-finals in 1999-2000 and 2002-03.
United eliminated Real in the 1967-68 semi-finals.
Real have won eight of their last nine home Champions League games while United have been victorious only twice in 20 visits to Spain.
United defender Rio Ferdinand, who played in the last-eight game against Real 10 years ago, told UEFA.com any contact he had with Ronaldo had dried up as the European showdown approached.
"We've had a few texts but when you get into a situation like this when you're coming up against a friend, all the texts and the conversations go to one side and you don't really speak until you actually get the game over and done with," he said.
Asked how United planned to thwart Ronaldo, he added: "You get as many people around the ball when he's got it as possible!
"But no, Madrid are that good a side you have to make sure you're set up right and that your team are in good positions all over the pitch to defend."
The return leg is at United's Old Trafford stadium on March 5.
Real: 41-Diego Lopez; 17-Alvaro Arbeloa, 3-Pepe, 4-Sergio Ramos, 5-Fabio Coentrao; 14-Xabi Alonso, 6-Sami Khedira; 22-Angel Di Maria, 10-Mesut Ozil, 7-Cristiano Ronaldo; 9-Karim Benzema
1-David de Gea, 2-Rafael, 3-Patrice Evra, 5-Rio Ferdinand, 15-Nemanja Vidic, 16-Michael Carrick, 23-Tom Cleverley, 8-Anderson, 7-Antonio Valencia, 10-Wayne Rooney, 20-Robin van Persie
Referee: Felix Brych (Germany)
($1 = 0.7474 euros)
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