Real Madrid centre-back Sergio Ramos has pulled out of Spain's Euro 2016 qualifiers later this week due to a shoulder injury, the national team said on Tuesday.
"Sergio Ramos is out of the squad due to shoulder pain and will be replaced by his (Real) team-mate Nacho (Ignacio Fernandez)," the Spanish said on their website.
Group C leaders Spain are set to host Luxembourg on Friday before traveling to Ukraine three days later.
A win in the first or draw in the second would be enough to ensure their passage to the finals in France, although they are already guaranteed at least a play-off spot.
Ramos's absence is another blow to Spain coach Vicente del Bosque with full-back Dani Carvajal, centre-back Inigo Martinez and midfielder Bruno Soriano all having already pulled out through injury on Monday.
They have been replaced by Mario Gaspar, Xabier Etxeita and Mikel San Jose respectively.