Liverpool's Luis Garcia and Andres Iniesta of Barcelona have withdrawn from Spain's squad to face Romania later in the week.
The friendly will take place in Cadiz on Wednesday, but both players have now been ruled out through injury.
Garcia is struggling with a persistent muscular complaint that ruled him out of Liverpool's defeat at Arsenal on Sunday, while Iniesta sustained a knee problem in Barcelona's 3-1 victory over Zaragoza at the weekend.
"Iniesta has an inflamed tendon in his left knee," Spain doctor Genardo Borras explained. "It is a minor injury but will require a couple of days' rest and so it has been decided that he should leave.
"We knew about Luis Garcia's injury on Friday.
"I spoke to him then and he told me it was an aggravation of an old muscle injury and that he wasn't going to play with his club. We decided it was best he didn't join up."
Spain coach Luis Aragones has opted against calling up replacements and will thus head into the friendly with an 18-man squad at his disposal.