Jose Mourinho's men are midway through their Champions League quarter-final with Tottenham Hotspur, though they travel to London on Wednesday with a handsome 4-0 advantage, and they welcome the La Liga leaders to the Bernabeu next Saturday.
Four days later the two teams meet again in the King's Cup final, and the likelihood of a Champions League semi-final clash between the Spanish giants drew closer when Pep Guardiola's side routed Shakhtar Donetsk 5-1 in the first leg.
If both teams progress, they would meet four times in 18 days.
Keeping his players fresh and injury-free for those matches while trying to keep alive their fading league title hopes will be Mourinho's priority in Bilbao.
Real trail Barca by eight points with eight matches left and have a tricky assignment at San Mames, traditionally one of the most hostile stadiums for them to travel to in Spain.
They have only beaten the Lions four times in their last 11 league visits and their fifth-placed hosts are eager to secure a place in European competition for next year.
Mourinho rushed Marcelo and Cristiano Ronaldo back from injuries against Spurs on Tuesday, and gave Kaka and Gonzalo Higuain run-outs after lengthy layoffs. Striker Karim Benzema missed out with a leg muscle strain but could return.
"It's for moments like these that they have spent so much money on their squad," Bilbao coach Joaquin Caparros, who guided his side to a 1-0 win in the same fixture last season, told sports daily Marca.
MAGNIFICENT SQUAD
"Now is the time for squads... and Madrid have a magnificent one. I'm sure they will put out a starting XI full of internationals.
"History shows that until it is mathematically impossible Madrid will not give up the league as lost."
Barca's push towards a third consecutive La Liga crown was helped by Real's shock home defeat by lowly Sporting Gijon last weekend, and that should serve as a reminder when they host basement side Almeria on Saturday.
The struggling south-coast club sacked Jose Luis Oltra on Tuesday and appointed Roberto Olabe as their third coach this season in a last-ditch attempt to stave off relegation.
Almeria, who have never even scored at the Nou Camp in the league, have one win from their last eight outings and are four points from safety.
One ray of hope for them, however, is that Barca goalkeeper Victor Valdes is suspended while reserve Jose Manuel Pinto pulled out of the Shakhtar game with a muscle strain. Youth-team player Ruben Mino could be called in as cover.
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