Diego Simeone's side are unbeaten in the previous five clashes between the capital clubs this season, following last year's defeat in the Champions League final
Atletico's record against their bitter rivals has been an excellent response to their defeat by Madrid in last season's Champions League final.
Los Blancos won 4-1 after extra time on that occasion but Atletico exacted a very minor form of revenge with a Supercopa success - which came after a 1-1 draw at the Santiago Bernabeu and a 1-0 win at the Estadio Vicente Calderon.
A league meeting followed in September, with goals from Tiago and Arda Turan giving Atletico a 2-1 win at the Bernabeu, and Diego Simeone's men were responsible for knocking Carlo Ancelotti's side out of the Copa del Rey's last 16 in January, winning 2-0 at home before a 2-2 draw in the return leg.
It all points to another mouth-watering encounter between the two sides.
Cristiano Ronaldo, scorer of 28 league goals this season, will return from suspension for the visitors, who lead the league by four points and are seven clear of third-placed Atleti.
They will be without James Rodriguez, though, after he fractured a metatarsal in Wednesday's 2-1 triumph over Sevilla in Madrid. Luka Modric (thigh) will also miss out.
James scored in the win, as did Jese Rodriguez, but the absence of the Colombian star is a significant blow in a clash against fresher opponents - Atleti did not play in midweek.
As always, there is no shortage of motivation for both sides but Atletico defender Diego Godin says that his team's excellent recent record against Ancelotti's men counts for nothing.
"We want to win - we always want to win. Even more against Real Madrid," he told reporters. "It's a different match and just because we won the previous matches doesn't mean we'll win this one.
"We must plan it well, follow the path we're on and that's what's going to bring us closer to the result we want. It's an important match against a direct rival, because of what's at stake in the league.
"Playing at the Calderon, with our people, we aspire to win."
Fernando Torres scored both goals in the 2-2 second-leg Copa draw and could be restored to the starting line-up after being an unused substitute in Atletico's 3-1 win at Eibar on Saturday.
Mario Mandzukic bagged a double on that occasion, while Antoine Griezmann netted a seventh-minute opener. Captain Gabi missed the match through suspension, which has now been served.