Real Madrid can take a giant step towards the title by beating Barcelona in La Liga on Sunday, while the Catalans will be looking to save their season.
Zinedine Zidane's side lead the Primera Division by three points from their fierce rivals, and also have a game in hand, so victory for the Blancos would put them in a commanding position to claim their first title since 2011-12.
Real are also in the Champions League semi-finals after knocking out Bayern Munich on Tuesday, but Barca were eliminated against Juventus the following night and will be playing to reignite their hopes of winning the Primera Division in Sunday's Clasico clash.
Raphael Varane and Pepe are both sidelined, leaving Real Madrid with only two central defenders available for the Clasico: Sergio Ramos and Nacho. Meanwhile, Gareth Bale is back in training after suffering a muscle problem in Munich and could return to the squad for Sunday's big match.
For Barcelona, Aleix Vidal is out for the remainder of the season, while Rafinha is also still sidelined and Javier Mascherano is doubtful.
Cristiano Ronaldo and Dani Carvajal are both just one yellow card away from a suspension and were rested for Real Madrid last Saturday at Sporting Gijon to avoid the possibility of a ban that would have seen them miss the Clasico. Nacho is also just one booking away from a ban and was fortunate to escape punishment for several fouls last weekend.
For Barcelona, Neymar misses out after he was hit with a three-match ban for his red card and subsequent protests in the 2-0 loss at Malaga earlier this month.
REAL MADRID POTENTIAL STARTING LINE-UP
Gareth Bale could return to the Madrid squad for the Clasico, but the Welsh winger is unlikely to be risked from the outset against Barcelona.
Isco is on good form and should start again, with Zidane likely to opt for the same side that played against Bayern.
That means the Spain midfielder will feature in an advanced role behind Cristiano Ronaldo and Karim Benzema.
BARCELONA POTENTIAL STARTING LINE-UP
Barcelona boss Luis Enrique is set to stick with 4-3-3 as Javier Mascherano is unlikely to return for this match at the Bernabeu.
That means Sergi Roberto and Jordi Alba should start in the full-back positions, with Andres Iniesta and Ivan Rakitic set to feature in a strong midfield.
The biggest decision of all will come further forward where either Arda Turan or Paco Alcacer will be charged with replacing the suspended Neymar. If fit, the Turkey midfielder is likely to be preferred.
BEST OPTA MATCH FACTS
Real Madrid are the Liga side that has beaten Barcelona the most often in the competition's history (72 times), while Barca (68 wins) are also the team that has beaten Madrid the most.
Los Blancos have not lost in the last two Liga Clasico clashes (won one, drawn one), their best unbeaten run against Barcelona in the Primera Division since March 2013, with Jose Mourinho as coach. However, both of those came at Camp Nou and Barca won 4-0 on their last visit to the Santiago Bernabeu.
Since becoming the fixture's all-time top scorer with a hat-trick in a 4-3 win in 2014 at the Bernabeu, Lionel Messi has played in six Clasico clashes without scoring, his worst run against Real Madrid (all competitions).
Cristiano Ronaldo has scored 16 goals in the Clasico in all competitions. Only Alfredo Di Stefano (18) and Messi (21) have scored more.
UK TV COVERAGE & KICK-OFF TIME
Real Madrid versus Barcelona kicks off at 20:45 CEST on Sunday and will be broadcast live, with coverage starting at 19:00 UK time on Sky Sports 1.