Atletico Madrid may have failed to defeat their local rivals since 1999, but with Los Rojiblancos eight points ahead of Mourinho's faltering charges in the La Liga table, they may feel they have a chance of setting the record straight, even away from home.
Jose Mourinho was booed by his own fans at the club's victory over Alcoyano at the weekend, and anything less than a win here will begin to make his position become doubtful. Los Merengues are suffering from a few injuries to key players at present, with Gonzalo Higuain, the most notable absentee, still not ready to return.
Atleti, in contrast, have been excellent so far this season, and by getting a result here they may dare to dream the impossible - that they could actually finish above their rivals. With the form of the likes of Radamel Falcao, it could be a realistic goal in the event of an away victory.
Karim Benzema will likely start for Mourinho up front as he recalls his big guns, but once again he will face a dilemme over what to do with Mesut Ozil and Luka Modric. Only one is likely to start in the number ten role, unless Mourinho can find a way to fit them both into the same team. With the lacklustre form his side are currently in, it may be worth looking at.
Real Madrid injuries and suspensions
Out: Raul Albiol (ankle), Gonzalo Higuain (ankle), Marcelo (foot), Michael Essien (knee.)
Atlético Madrid injuries and suspensions
In doubt: Cristian Rodriguez (thigh).
Raul Albiol picked up an injury in the Copa del Rey clash against Alcoyano and will be unavailable for selection, along with long-term absentees Higuain, Marcelo, and Essien.
Los Rojiblancos welcome back Thibaut Courtois from injury and Mario Suarez from suspension, although Cristian Rodriguez is highly unlikely to be available.
Match Date\Time: Saturday, 10 p.m. local, 9 p.m. BST, 4 p.m. ET
Venue: Santiago Bernabeu, Madrid, Spain
TV: beIN Sport (U.S. English) beIN Sport en Espanol (U.S. Spanish), Sky Sports 1 (U.K.)