The Real Madrid man had only just returned from surgery before suffering an ankle sprain - one which kept him out of the weekend's win over Celta Vigo - and Luis Enrique may not be tempted to take any risks over his fitness.
As a result, Inigo Martinez looks guaranteed to start in defence, while Diego Llorente and Eric Garcia - neither of whom have played much football this term - could battle it out for the final centre-back spot in Enrique's side.
With Sergi Roberto, Hector Bellerin, Dani Carvajal and Jesus Navas all not in the squad, Sporting Lisbon's Pedro Porro could be handed his first-cap at right-back, while Jordi Alba should be given the nod on the left over Jose Gaya.
Barcelona starlet Pedri is certainly in contention after breaking into the Blaugrana's first team, while Sergio Canales and Fabian Ruiz are both viable options, but Enrique may place his faith in the experienced Thiago against Greece.
Ferran Torres struck a hat-trick against Germany in Spain's most recent fixture and his struggles at Manchester City should therefore not matter too much in the grand scheme of things, while Alvaro Morata and Mikel Oyarzabal are the most likely candidates to complete the attack.
Spain possible starting lineup:
De Gea; Porro, Martinez, Llorente, Alba; Rodri, Thiago, Koke; Torres, Morata, Oyarzabal