Already four points ahead of the Blaugrana, a win for the hosts will open up a seven-point gap and effectively end Barca's hopes of keeping the trophy in Catalonia for another season.
However, with only two defeats in their last 10 trips to the Spanish capital, Barca boast one of the best records of any visiting side.
Tata Martino also remains unbeaten in the big fixtures this season, and if he can mastermind another victory, Barcelona will be right back in the title race.
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Los Blancos suffered a terrible blow in midweek after losing young starlet Jese to a season-ending injury.
It's a cruel blow for both player and club, given the form he had shown throughout the season. Madrid manager Carlo Ancelotti told a news conference, via Reuters:
He has had bad luck and everyone at Real Madrid has had bad luck because we will lose a young player who has been doing very well this season.
We are sad and it has affected us a lot but it could be a chance for him to build strength of character. We have to stay positive.
On the flip-side, Madrid will be boosted by the return of in-form Frenchman Karim Benzema.
According to Spanish daily AS, (h/t Matt Law of SportsMole), the thigh swelling suffered by Benzema in his accidental clash with team-mate Cristiano Ronaldo has now subsided, and the player is training normally ahead of the top-of-the-table clash.
Barcelona meanwhile have no fitness concerns of their own.
Club captain Carles Puyol is still sidelined but was unlikely to be considered for this match anyway, given it's magnitude and his own lack of match fitness.
Gerard Pique was left out of Barca's rout of Osasuna last weekend because of an ankle complaint, but as Tom Conn of Inside Spanish Football reports, Pique is back in training and ready to assume his position in the heart of the Catalan's defence.
The Portuguese has scored nine in his last six matches in all competitions, per WhoScored.com, with Messi contributing a slightly less prolific seven.
Interestingly, the Argentine has the opportunity to rewrite the history books for the second week in succession.
After overhauling Paulino Alcantara's all-time goals record for Barcelona in their 7-0 romp against Osasuna last weekend, Messi goes hunting for the single goal that will see him become the outright leading scorer in these epic contests.
He is currently tied on 18 with Madrid legend Alfredo di Stefano, with Ronaldo coming up fast on 12.
Aside from El Clasico goals, Messi also leads his nemesis in the assists column 11 to 1, however, there is no doubt that Ronaldo has been the more decisive in the most recent games between the two sides.
That could well prove to be the case again this time, with Gareth Bale and Benzema providing more than able support to Madrid's main man since their last loss in La Liga, coincidentally in the last Clasico.
Neymar enjoyed a fine start to his Barca career including a debut Clasico goal in October, however, he has been nothing like the same player since returning from injury and it's debatable whether he can offer Messi the same type of support.
Prediction: Real Madrid 1-1 Barcelona