Isco has withdrawn from the Spain squad ahead of their friendly against Chile on Tuesday after he failed to shake off an injury.
The attacking midfielder had been struggling with a knock to his left ankle which saw him pull out of training last Thursday and miss la Roja's World Cup qualifying victory over Finland in Helsinki.
There had been hopes that the 21-year-old may be fit to face the South Americans in Switzerland but Vicente del Bosque has allowed the player to head back to Madrid for further treatment after undergoing medical tests with the Spanish team doctors on Sunday afternoon.
Del Bosque has decided against calling up a replacement for the Real Madrid man and the 62-year-old may even be prepared to let a few other stars miss the trip to Stade de Geneve, with Barcelona keen to see the trio of Jordi Alba, Xavi, and Iniesta rested as they prepare for the Champions League group stages.
The news comes as another blow for Real Madrid boss Carlo Ancelotti during a disruptive international break, having already received confirmation that Marcelo has withdrawn from the Brazil squad.
The full-back pulled up with a thigh injury during the Selecao’s 6-0 demolition of Australia and will miss the friendly with Portugal.