Pique worked in the gym on Friday and Vicente del Bosque later left him out of the Spain squad for their World Cup qualifiers.
"He is doing all he can to be ready," Xavi told a news conference on Friday. "He has gone 10 days without training so it is tough. I think it is 50-50 whether he plays or not."
With Carles Puyol out (dislocated elbow) midfielders Javier Mascherano and Alex Song are expected to reprise their unconvincing partnership at the back again.
Barca are two points clear of second-placed Atletico Madrid at the top of La Liga with a perfect 18 points from six games, and are eight ahead of sixth-placed Real.
"It would be a tremendous boost to morale to win," Xavi said. "It would be our seventh straight victory in La Liga and would leave Madrid 11 points behind us."
Real Madrid coach Jose Mourinho has no injury worries ahead of the Clasico, and his main concern would appear to be which of his creative midfielders to play.
Luka Modric, Mesut Ozil, and even Kaka, who made his first start this season against Ajax on Wednesday, are all competing for the playmaker role.