It will be the fifth Clasico since Ronaldo departed Real Madrid in 2018 and Spain's most prestigious fixture has not been quite the same without him, a duel lost between the world's two greatest players.
But Benzema's surge means Madrid have rediscovered their punch up front while Barcelona know their opponents now possess a player who may not be able to rival Messi but, like him, could win this match on his own.
"We often talk about Karim these days," said Real coach Zinedine Zidane after Benzema scored against Espanyol this month.
"He's matured and I think that's what makes the difference.
"We all have small defects, things to improve. But what he is asked to do is to chase and he does it, to score goals and he does it. I can't ask anything more of him, only that he continues like this.
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When Ronaldo was sold to Juventus, the theory was Benzema would have to be more prolific and Gareth Bale more prominent, a chance for the Welshman to finally to revel in the limelight.
In truth, only one of them has fulfilled those hopes even if Bale's trajectory has again been flattened by fitness issues and Benzema's only began to turn upwards after Madrid's disastrous start to last season, which saw two coaches sacked in five months.
Yet few could argue he has been Real Madrid's best player for the majority of 2019, ahead of Eden Hazard, signed for 100 million euros last summer, and Luka Modric, last year's winner of the Ballon d'Or.
He has been more consistent than Sergio Ramos and more straight-forward than Bale, despite the possibility of a criminal trial still hanging over him for his alleged role in the blackmail case involving Mathieu Valbuena in 2015.
That controversy still denies Benzema a place in the French national team and while Didier Deschamps' blackout has been vindicated by France's World Cup triumph last year, they continue to miss out on one the world's most lethal centre forwards.
"I work for Madrid," Benzema said on Sunday after he scored Madrid's 95th-minute equaliser against Valencia. "What is said over there I don't listen to."
Perhaps that has been to Madrid's advantage and the test now for this resurgent Benzema is to define the biggest games in the way Messi has done his whole career.
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This season, Benzema has 16 goals in 21 matches -- more than Messi's 14 in 16 -- and he has nine in his last eight.
Since Zidane returned in March, Benzema has 24 goals in 30.
There is no doubt his performances have improved since Zidane came back. For many years Benzema was the foil to Ronaldo but he has become the complete package on his own -- a provider, chaser and scorer.
"What has changed is the number of goals," Benzema said. "I have a lot of confidence in myself."
Zidane has been asked many times about Benzema's contributions and often he says what he likes most is the 31-year-old's focus on the team.
"We always talk about goals, but it's what he does for the others that I hold onto most," said Zidane last month.
For Messi, the emphasis appears reversed as Barcelona increasingly spend matches trying to find ways to unleash their magic number 10.
Invariably, Messi delivers, not just in the routine fixtures but when it matters most. In 41 meetings with Real Madrid, he has 26 goals. In 35, Benzema has nine.
Fresh from winning a record sixth Ballon d'Or earlier this month, not to mention scoring eight goals and two hat-tricks in his last six games, Messi is in scintillating form.
But Benzema is in the form of his life too and, at this moment, it could be him who owns this first Clasico of the season, that will decide who goes top of La Liga.
Real Madrid are counting on it.
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