The clash between nine-times winners Real and seven-times champions Milan is a highlight of the third set of group games in which holders Barcelona also hosting Russia's Rubin Kazan.
Liverpool's home encounter with Olympique Lyon is another standout given the English side's recent poor form.
Milan know exactly how Rafael Benitez is feeling having lurched from one setback to another both on and off the field since angering fans by selling Brazil's Kaka to Real in June.
The 1-0 home defeat by FC Zurich in their last Group C game was one of a string of bad results and despite Sunday's 2-1 win over AS Roma, rookie coach Leonardo remains under pressure.
"After Kaka's sale it's normal that there is a moment of adaptation, but it's not an excuse," Leonardo told reporters.
"We go forward with our objectives. This year we started out knowing that we have to reorganise ourselves."
Kaka has said he will not celebrate if he scores against his former side, who won the 2007 trophy thanks in part to the playmaker's inspirational displays.
The Brazilian will be even more centre stage because Cristiano Ronaldo is still out for Real with an ankle injury, although he was not missed in Saturday's 4-2 win over Valladolid.
Zurich also entertain pointless Marseille on Wednesday.
BEACH BALL
Tuesday's focus will be on five-times winners Liverpool, beaten by Fiorentina in their previous Group E match and faring no better in the Premier League recently.
Fernando Torres and Steven Gerrard were injured for Saturday's 1-0 loss at Sunderland where they conceded when a shot deflected in off a beach ball thrown from the crowd.
"We'll see how they progress. They are improving but it's difficult to say if they can be available," Benitez said about the chances of his best two players facing pacesetters Lyon.
Fiorentina head to Hungary's Debrecen buoyed by Saturday's battling 1-1 Serie A draw at Juventus.
Ciro Ferrara's Juve have not won in five games in all competitions but will expect to break the sequence in Wednesday's Group A match with Maccabi Haifa in Turin.
Bayern Munich and Girondins Bordeaux meet in France.
Also on Wednesday, 2008 winners Manchester United travel to CSKA Moscow with striker Wayne Rooney a doubt while VfL Wolfsburg host Besiktas in the other Group B game.
Striker Didier Drogba is still suspended for leaders Chelsea when they welcome Atletico Madrid in Group D where Porto meet APOEL Nicosia at home.
Barcelona drew 0-0 at Valencia on Saturday to drop points domestically for the first time this term and will be without the injured Thierry Henry for Tu
