Spain's two most powerful clubs have been locked together at the top of the table for a month, since Barca were held 2-2 in Almeria and relinquished first place to their arch-rivals on goal difference.
The champions travel to face the leaders tied on 77 points with eight matches left to play, a massive 21 points ahead of third-placed Valencia after steamrollering most of their opposition this year.
Real are on a 12-match winning streak in the league and have won all their home matches, while Barca have lost only once all season, which makes the second 'Clasico' all the more significant.
After Saturday, should they remain level on points, the head-to-head record between the clubs takes priority over goal difference in deciding the top spot.
Barca hold the upper hand in that contest after their 1-0 win at the Nou Camp back in November.
A better head-to-head record over Barca handed Real the league title under Fabio Capello back in 2007, and the nine-times European champions are desperate to keep alive their only hope for silverware this year.
There has been a constant stream of players and dignitaries playing down the significance of this encounter, warning of the seven remaining games each has to play after it.
But the message has failed to get through to Sports daily Marca, who have billed the match as the 'Game of the Millennium'.
"I don't think it will be decisive but it will be very important in resolving the outcome of the league," Xabi Alonso told the same paper.
INJURED PRIDE
There is a lot of injured pride at stake in Madrid as well since they were humiliated 6-2 in front of their own fans in the same fixture last year.
Lionel Messi destruction of Arsenal in the Champions League on Tuesday would have made uncomfortable watching for the Real players but their midfielder Guti dismissed the idea that his side would have a special plan to stop the Argentine.
"We don't need an 'anti-Messi' plan. We need an 'anti-Barca' plan because they aren't only about Messi. To worry about one player would be ridiculous," he told reporters on Wednesday.
"Cristiano Ronaldo is as good if not better than Messi," he added.
"We are a different team to last year. In Barcelona (in November) there was very little between the sides. There has never been a 'Clasico' so evenly-balanced."
Brazilian playmaker Kaka (thigh) and midfielder Royston Drenthe (thigh) are unlikely to recover from their respective injuries in time to make Manuel Pellegrini's squad.
Barca proved they are firing on all cylinders when they progressed to the last four of the Champions League during the week, and are awaiting news on two important players.
Pep Guardiola has given his side Thursday off, and could have defender Gerard Pique (thigh) and striker Zlatan Ibrahimovic (calf) back from injury just in time for Saturday although left back Eric Abidal is out with a thigh injury.
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