Both teams head into the game locked on 35 points at the top of the table and having been held to draws at the weekend.
Barca have few injury problems going into the match, other than Ousmane Dembele, so let’s have a look at how they might line up.
Barca’s defensive injuries have cleared up with Jordi Alba and Nelson Semedo both back to full fitness after being sidelined for a little while.
Semedo has yet to start since coming back so could be a substitute again on Wednesday with Sergi Roberto continuing at right-back.
Ernesto Valverde needs to choose two of Gerard Pique, Clement Lenglet and Samuel Umtiti at centre-back, while Marc-Andre ter Stegen will of course be in goal.
Ivan Rakitic seems to have regained his place back in the starting XI and looks set to start alongside Sergio Busquets and Frenkie de Jong.
Arturo Vidal and Carles Alena are also options for Valverde, and both have seen games time in recent matches but are likely to be on the bench.
Arthur is still out injured with the latest reports suggesting he will not be back in action until after the Christmas break.
Anything other than a frontline of Lionel Messi, Luis Suarez and Antoine Griezmann will be a surprise against Los Blancos.
Dembele’s injury has left the club a little short of other options in attack, although Ansu Fati and Carles Perez should make the bench and may come on at some point.
Possible XI: Ter Stegen; Roberto, Pique, Umtiti, Alba; Rakitic, Busquets, De Jong; Messi, Suarez, Griezmann.
How do you think Barcelona should line up against Real Madrid? Let us know your thoughts, predictions and teams in the comments below!