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".
The former Spurs man has been struggling to shake off the groin problem for a number of weeks. He originally picked up the issue 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.
Wales are currently second in their Nations League group, just one point behind leaders Denmark, with Republic of Ireland in last spot, having lost one and drawn one of their opening two fixtures.
The absence of Bale is a hefty blow for the Welsh, who know that a defeat in Dublin would see Martin O’Neill’s side leapfrog them in the table.
Along with his talismanic attacker, Giggs has also lost Ethan Ampadu and Chris Mepham to injury ahead of the Republic of Ireland fixture.
Star man Bale helped Wales on their way to a 4-1 win between the two sides in their first Nations League meeting in September.
However, their most recent performance was a lot more disappointing, with Giggs’ side falling to a defeat of the same scoreline to Spain.
The 29-year-old will be hoping to return to full fitness as soon as possible, with Real Madrid currently on a run of form that has seen them go six hours and 49 minutes without a goal, their worst goalless run for 33 years.