Gareth Bale will miss Wales' two friendly matches against France on 10 November and Panama four days later.
The 28-year-old forward is back in training with Real Madrid after a calf injury but will not feature in their La Liga game against Las Palmas on Sunday.
Bale has not played since 26 September but had been named in Wales' squad.
"Gareth is not going to be in the squad (to face Las Palmas) and he is not going to go with his national team," said Real manager Zinedine Zidane.
"Right now he has had two training sessions with us and what we want is for him to remain with us so that he is ready as soon as possible."
Wales manager Chris Coleman had already warned that it would be down to Bale's club side to determine his availability to face France in Paris and Panama in Cardiff.
Bale sustained his injury during Real's Champions League victory over Borussia Dortmund six weeks ago.
He has since sat out seven matches for the European champions and missed Wales' final two World Cup qualifiers against Georgia and the Republic of Ireland last month, as the Dragons failed to qualify for the 2018 finals in Russia.
Coleman has called up Barnsley striker Tom Bradshaw as a replacement for Bale, while Wigan Athletic's Lee Evans has been added in place of Ipswich Town midfielder Emyr Huws who has an Achilles injury.
West Bromwich Albion striker Hal Robson-Kanu has also withdrawn and has been replaced by Barnsley's Lloyd Isgrove who also later withdrew.