The youngster was handed a golden opportunity to show that, just like the former Dutch midfielder, he can be a star under Carlo Ancelotti - but he flopped against his old side.
The 21-year-old had enjoyed two magnificent seasons at La Rosaleda, developing into one of Europe's most exciting young midfielders. After inspiring the Andalusians to the Champions League quarterfinals last year, Isco became the first signing of Carlo Ancelotti's Madrid reign for a fee of 30 million euros.
He was expected to be a key man for los Blancos following the sale of Mesut Ozil to Arsenal but, despite a bright start to his career at Santiago Bernabeu, Ancelotti's decision to switch from Jose Mourinho's 4-2-3-1 system to a 4-3-3 forced Isco out into the cold.
An offensive player who excels in the space between midfield and attack, the 4-3-3 meant there was no natural position for the Euro Under-21 champion. Unless, of course, he could adapt to the new formation.
Last week Ancelotti spoke of his hope that Isco could reinvent himself from a trequartista into a deeper midfielder, just as Clarence Seedorf had under the Italian at AC Milan.
"We have spoken for a month about how he can adapt," explained Carletto. "We haven't been able to play with him in his usual position.
"He played very well against Schalke and Atletico Madrid. He is closer to starting. I had a similar case: Seedorf was an attacking central midfielder who, with sacrifice, played in a different position. Isco can do what Seedorf did."
With Angel Di Maria one yellow card away from missing next weekend's Clasico, and virtually begging Ancelotti not to start him, Isco was handed a golden opportunity against his former side to prove that he is indeed flexible. He lined up in Madrid's midfield three alongside Luka Modric and Xabi Alonso - who was making his 150th league appearance for the team.
But the young Isco showed that he is not ready to replicate what the great Seedorf did a decade ago. He was caught on the ball on numerous occasions, repeatedly made the wrong decisions when in possession and dismally failed to interpret his role tactically - unsure of when to push or hold. All this despite Madrid dominating the early stages, with Ronaldo scoring what proved to be a fantastic winner and Gareth Bale being denied a stonewall penalty after a challenge by Marcos Angeleri.
When Karim Benzema limped off on the half-hour mark with a thigh injury - thus putting the Frenchman's participation against Barcelona in doubt - Ancelotti decided he had already seen enough of Isco in midfield. The youngster was shifted into attack and Di Maria joined Modric and Alonso in the center of the park.
Isco's experience as a 'False 9' was just as unhappy. He failed to hold onto the ball or link up with Bale and Ronaldo as Madrid lost its attacking impetus. His evening of disappointment was completed after the break when Di Maria embarked on an incredible Diego Maradona-like solo run and slipped Isco through on goal. With just Willy Caballero to beat and a favorable angle, the Spain international never looked like scoring and blazed over.
Ancelotti put an end to his misery just after the hour, with Jese entering in his place. Isco's frustrations were clear to see as he dejectedly made his way towards the bench.
His glaring miss could have proved very costly as Madrid suffered in the closing stages, the home side piling on the pressure in search of an equalizer. The league leader held on, though, to extend its advantage at the top of the table and create a seven-point gap between itself and Barcelona - with the Blaugrana playing their game in hand against Osasuna on Sunday.
Madrid approaches the Clasico in unstoppable form - the club is now unbeaten in 30 games in all competitions, and has won 16 and drawn two from its 18 matches in 2014. Life is not so rosy for Isco, though. Saturday was his big chance to show that he is ready to adapt to Ancelotti's Madrid and he blew it.
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