Barcelona midfielder Xavi is reportedly suffering from tendonitis
Xavi is a surprise omission from Spain coach Vicente del Bosque's squad for their Euro 2012 qualifiers against Lithuania and Scotland next month.
The Barcelona playmaker, who is said to be suffering tendinitis, joins fellow midfielder Cesc Fabregas and defender Raul Albiol on the injury list.
Fabregas damaged a hamstring during Arsenal's 1-1 draw with Sunderland on 18 September.
He was expected to be out for two to three weeks.
Albiol misses out despite returning to training with Real Madrid this month after a ligament injury picked up during the summer.
Meanwhile, a Barcelona spokesman could not immediately confirm the nature of Xavi's injury despite media reports in his homeland blaming tendinitis.
World champions Spain began their European title defence with a 4-0 win in Liechtenstein earlier this month.
They play Lithuania in Salamanca on 8 October and Scotland in Glasgow four days later in the latest round of Group I games.
Scotland lead the group from Lithuania thanks to goals scored, with Spain a point behind but with a game in hand.
Goalkeepers: Iker Casillas (Real Madrid), Victor Valdes (Barcelona), Pepe Reina (Liverpool)
Defenders: Alvaro Arbeloa (Real Madrid), Sergio Ramos (Real Madrid), Carles Puyol (Barcelona), Gerard Pique (Barcelona), Carlos Marchena (Villarreal), Joan Capdevila (Villarreal), Nacho Monreal (Osasuna)
Midfielders: Xabi Alonso (Real Madrid), Sergio Busquets (Barcelona), Santi Cazorla (Villarreal), Andres Iniesta (Barcelona)
Forwards: Pedro (Barcelona), Jesus Navas (Sevilla), David Villa (Barcelona), David Silva (Manchester City), Fernando Llorente (Athletic Bilbao), Fernando Torres (Liverpool).