Hosts Atletico know that they cannot afford a defeat which would leave them six points behind their eternal rivals in the title race, while Real Madrid will be aiming for the win which would bring them that healthy margin over their neighbours.
Paddy Power offer the Rojiblancos at 9/4 (3.25) for the win while Carlo Ancelotti's men can be backed at 11/10 (2.10). A draw is available at 5/2 (3.50).
Madrid of course triumphed in the most recent meetings between the two sides just a few weeks ago, recording a 5-0 aggregate win over the two legs of their Copa del Rey semi final, meaning that Atletico have still failed to beat Los Blancos at the Calderon for 15 years.
Given Madrid's current run of 26 games unbeaten and the stunning way they demolished Schalke 6-1 in the Champions League midweek, Diego Simeone's men will have to go some way to change that record.
The best bet for this blockbuster clash could come from the goal scorer markets, and it is hard to look past the price of 4/5 (1.80) for Cristiano Ronaldo to net at any time.
The Ballon d'Or winner scored twice in midweek and could conceivably have netted five, with Ronaldo seemingly thriving in hostile atmospheres.
He has scored five times in his last two visits to the Calderon and netted nine goals in his last seven Madrid derbies so both recent form and history look to be supporting this bet.
Most weeks Ronaldo is offered at half this price to score, so backing him to net against an Atleti side which have lost four of their last six games looks like a great bet and one which shouldn't be ignored.
|Cristiano Ronaldo to score at 4/5 (1.80) 2.5pt stake with Paddy Power|
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Phil Kitromilides is a sports journalist and TV presenter in Madrid