Alun Wyn Jones is out of Ospreys' Heineken Cup clash in Treviso and Wales' 3 December Test with Australia in Cardiff because of a dislocated toe.
The 26-year-old second-rower will undergo surgery on the toe he injured in training this week and Ospreys hope Jones will return before Christmas.
Wales coach Warren Gatland may have a lock crisis as Luke Charteris is a doubt due to a wrist injury.
Ryan Jones replaces Jones for Ospreys' European visit to Treviso on Saturday.
And the versatile 30-year-old is favourite to partner Bradley Davies in the second row for the Australia showdown at the Millennium Stadium.
Charteris and Alun Wyn Jones were Gatland's first-choice second row pairing when Wales finished fourth at the Rugby World Cup in New Zealand.
So Jones' absence is another blow for the Wales coach.
"Alun-Wyn suffered a foot injury in training this week," Ospreys head physiotherapist Chris Towers said.
"As a result, he is going to require surgery to repair soft tissue damage, which will be carried out over the weekend.
"Once he starts his post-op rehab work we will be in a better position to predict recovery timelines."
Flankers Dan Lydiate and Justin Tipuric are also both fitness doubts for the World Cup third-place play-off repeat in Cardiff.
Bayonne scrum-half Mike Phillips has hinted he may miss the December international because non-Welsh clubs do not have to release their players for games outside the International Rugby Board window, unless individual contracts allow.
Perpignan fly-half James Hook will definitely miss the fixture because the game is not an IRB sanctioned game.
And Clermont Auvergne full-back Lee Byrne, Exeter prop Craig Mitchell and Sale Sharks pair Andy Powell and Dwayne Peel are also doubtful for the same reason.
Gatland's Wales squad meet on Monday to begin their Australian preparation but the Kiwi coach also has fitness worries over Leigh Halfpenny (ankle), Huw Bennett (neck) and Jonathan Thomas (thigh).