Gareth Bale has pulled out of the Wales squad and returned to Real Madrid to continue his recovery from a groin injury.
The 29-year-old winger sat out last week's friendly defeat to Spain and will now miss Tuesday's key Nations League match against Republic of Ireland.
Ryan Giggs had acknowledged Wales' record goalscorer was unlikely to be risked in Dublin despite describing the issue as "not serious".
Bale originally picked up the groin problem in last month's Madrid derby and limped out of the 1-0 loss to Alaves prior to the international break.
"Gareth Bale has returned to his club this afternoon and will not travel to Dublin with the rest of the squad," the Football Association of Wales wrote on Twitter.
Along with his talismanic attacker, Giggs has also lost Ethan Ampadu and Chris Mepham to injury ahead of the Republic of Ireland fixture.