Mark Jones joins Adam Jones, Lee Byrne and Mike Phillips on the sidelines
Wales wing Mark Jones has been ruled out for a minimum of three months.
The Llanelli Scarlets captain underwent keyhole surgery to repair torn cartliage in his right knee on Tuesday after an injury in training.
Jones will miss the Scarlets' final Heineken Cup pool games and is a major doubt for Wales' Six Nations campaign.
Scarlets coach Nigel Davies confirmed: "It is very disappointing and unlucky for Mark at this particular time. It's one of the curses of modern day rugby."
Wales coach Warren Gatland revealed injury-prone Jones suffered a fresh knee injury on the bags in training on the weekend.
Morgan Stoddart, Jones' Scarlets team-mate, has been called into Wales' autumn Test squad to replace 29-year-old Jones.
"Mark is one of the most positive players I know in terms of coming back from injury," Davies continued.
"He deals with these set backs more positively than most people.
"He has been a huge asset for already for us this season in his role as captain and is totally respected by all the players.
"Despite being injured Mark will be back with the region for his recovery and during this time will continue to play a key leadership and motivational role off the field with the players as well as working closely with coaching staff and Scarlets management."
Jones, the 2008 Grand Slam winner, joins fellow Welsh internationals full-back Lee Byrne, scrum-half Lee Byrne and tighthead prop Adam Jones on Gatland's injured list.
The 47-times capped international, who made his Wales debut against England in 2001, suffered consecutive knee injuries - and required major reconstructive surgery - so missed the 2003 Rugby World Cup due to his long-standing knee problems.
Wales squad for autumn international series:
Backs: Dan Biggar James Hook, Shane Williams (Ospreys); Gareth Cooper, Jamie Roberts, Tom Shanklin, Tom James, Leigh Halfpenny (Blues); Martin Roberts, Stephen Jones, Jonathan Davies, Morgan Stoddart (Scarlets); Dwayne Peel (Sale).
Forwards: Paul James, Duncan Jones, Craig Mitchell, Huw Bennett, Alun Wyn Jones, Ryan Jones (capt), Jonathan Thomas (Ospreys); Gethin Jenkins, Bradley Davies, Andy Powell, Sam Warburton, Martyn Williams (Blues); Matthew Rees, Dafydd Jones (Scarlets); Luke Charteris, Dan Lydiate (Dragons).