Barcelona, beaten 2-1 at home by debutants Rubin Kazan last time out, visit the same team on Wednesday knowing that another defeat would put them out of the top two in Group F.
The group stage's fourth round of matches could also be crucial for the fortunes of former champions Bayern Munich and Liverpool, currently out of the top-two places in their groups.
Bayern host French champions Girondins Bordeaux in Group A and Liverpool, who have lost six of their last seven games, travel to Olympique Lyon in Group E.
Real playmaker Kaka returns to the San Siro stadium for the first time as the Spaniards visit his old club hoping to avenge their 3-2 defeat at the Bernabeu.
That result prompted a dramatic turnaround in the fortunes of the two sides.
AC Milan's rookie Brazilian coach Leonardo, who went into the game under severe pressure, is now sitting pretty after an unbeaten seven-match run while opposite number Manuel Pellegrini is feeling the heat.
"Real is a game which you especially prepare for. We hope to maintain our high level of play," Leonardo said.
Pellegrini's position was questioned after Real's embarrassing 4-0 defeat by third-tier Alcorcon in the King's Cup made it three games without a win.
A 2-0 La Liga win over Getafe on Saturday, courtesy of two goals from unsung Argentina striker Gonzalo Higuain, calmed the waters a bit.
But defeat on Tuesday could see another storm brewing for Pellegrini, who will again be without injured Cristiano Ronaldo.
"The papers have been full of names of great coaches but we are happy with Pellegrini and we are sure he will finish the season positively," club president Florentino Perez told Italian television.
