Spain coach Vicente Del Bosque on Friday named a 21-man squad for the friendly against Uruguay on February 6, with Malaga starlet Isco and Chelsea full-back Cesar Azpilicueta included for the first time.
However, the reigning European and world champions will take on the 2011 Copa America winners in Doha, Qatar without another Chelsea player, as striker Fernando Torres was left out.
Isco, who recently signed a contract extension with Malaga, is just 20 but is one of the most exciting prospects in the Spanish game right now, while right-back Azpilicueta has nailed down a regular place in the Chelsea side since arriving from Marseille last summer.
Carles Puyol returns to the squad after a dislocated elbow denied him the chance to win his 100th cap in La Roja's final game of 2012.
Nacho Monreal is also called up a day after sealing his transfer from Malaga to Premier League side Arsenal.
As well as Torres, Valencia striker Roberto Soldado is also missing from the attack, while Real Madrid goalkeeper Iker Casillas is absent due to injury.
The game against Uruguay will serve as preparation for their World Cup qualifying double-header against Finland and France next month.
Goalkeepers: Victor Valdes (Barcelona), Jose Manuel Reina (Liverpool)
Defenders: Sergio Ramos, Alvaro Arbeloa (both Real Madrid), Gerard Pique, Carles Puyol, Jordi Alba (all Barcelona), Cesar Azpilicueta (Chelsea), Nacho Monreal (Arsenal)
Midfielders: Andres Iniesta, Cesc Fabregas, Sergio Busquets, Xavi Hernandez (all Barcelona), Santi Cazorla (Arsenal), Francisco Alarcon Isco (Malaga), Xabi Alonso (Real Madrid)
Forwards: David Villa, Pedro Rodriguez (both Barcelona), David Silva (Manchester City), Alvaro Negredo (Sevilla), Juan Mata (Chelsea).