David Beckham will return to Old Trafford for the first time in seven years as AC Milan visit his old club Manchester United, who may be without injured Wayne Rooney, in another of this week's round-of-16 second legs.
In-form Arsenal host two-times winners Porto and Bayern Munich visit Fiorentina in the remaining matches, both of which featured highly-controversial refereeing decisions in the first leg.
Referees are likely to be even more under the spotlight this week after soccer's rule-makers, the International Football Association (IFAB), on Saturday decided to indefinitely reject the use of goal line technology, standing firm in the face of pressure from players, coaches and the media.
With the final at the Bernabeu, much of the Spanish media see a 10th European title as almost an obligation this year for a Real team which includes Kaka and Cristiano Ronaldo.
Real have scored 14 goals in winning their last three La Liga games but on Wednesday must overcome a 1-0 deficit against a Lyon side, which has kept a clean sheet in its last six matches, including the first leg last month.
The last player to score against Lyon was Paris St Germain's Mevlut Erding in the 10th minute of a Ligue 1 game on Jan. 31.
"It will be a failure to not get past this round against opponents such as Lyon, who are good but not among Europe's big teams," midfielder Guti told the sports daily Marca.
"Wednesday's game is a final for us," added Xabi Alonso after Saturday's 3-2 win over Sevilla, when Real came from 2-0 behind.
Beckham is expected to get a warm reception at Old Trafford in the other of Wednesday's games although he may have to settle for that with his team trailing 3-2 from the first leg at the San Siro.
He is far from certain to start either, having begun several recent games on the substitutes' bench.
Milan's Brazilian coach Leonardo is still hopeful the seven-times champions can turn the game around.
"Football is giving us a great opportunity. It's extraordinary to go to Old Trafford having to win in an important way," he said.
"I don't just mean winning 2-0. I mean victory, going there to score goals and play a game against a Manchester side who have their style.
Rooney, who scored twice in the first leg, suffered a knee injury during England's 3-1 friendly win over Egypt on Wednesday.
"It's one of these bad bits of luck you get - the Wembley pitch has just killed him," said manager Alex Ferguson.
Arsenal, who have Cesc Fabregas doubtful with a hamstring injury, go into Tuesday's match 2-1 down to a Porto goal which had Arsene Wenger fuming.
The Arsenal manager was incensed after Colombian striker Radamel Falcao's goal from a quickly taken indirect free kick was allowed to stand.
"First of all, it has to be clarified how UEFA nominate referees for games. They have to be much more open on how they rate their referees. Nobody really knows how they name their referees," he told a news conference a couple of days after the game.
"Where is the ranking of the referees? I believe too much has gone on in the last 30 years. What has happened is not good for football." Four-times champions Bayern, unbeaten in 18 games in all competitions, take a 2-1 lead to Fiorentina thanks to a last-gasp Miroslav Klose goal which both coaches agreed was well offside.
