Gethin Jenkins has been ruled out of Wales' Six Nations opener against Ireland on Sunday week with a knee injury.
Coach Warren Gatland, speaking at Wednesday's tournament launch in London, also revealed that Rhys Priestland and Dan Lydiate are major doubts for the trip to Dublin, but that Jamie Roberts is expected to play.
Jenkins failed to join his team-mates at Wales' training camp in Poland this week in order to receive treatment on the injury he sustained while on Heineken Cup duty for Cardiff Blues last Sunday.
The earliest the Lions prop could return is for the clash with England on February 25, with Paul James the leading contender to replace him.
"Gethin is struggling and could be out for four to five weeks," said Gatland.
"He's is a huge loss for potentially the first two games of the tournament.
"He's been playing exceptionally well for the Blues in the last month or so.
"He's a world-class player. He's got a very good rugby brain and is able to assess things on the field. He's almost like a coach on the field.
"You get a lot of information from him at half-time, what's going right or wrong, tactically where we need to change."
Gatland is likely to start James Hook at first five-eighths against Ireland should Priestland, who emerged as one of the stars of last year's World Cup, fail to recover from his knee injury.
"Rhys is struggling for the first game. We're assessing him day by day," said Gatland.
"Rhys was probably the find, if not the best, fly-half at the World Cup. He really does fit the type of game we want to play.
"His kicking game and vision are excellent. He stretches opposition defences as well because he's not afraid to run.
"There's a very good balance to his game. You can't underestimate the space he created for our midfield at the World Cup.
"He was one of the reasons we saw some really big performances from Jamie Roberts, Jon Davies and Scott Williams. He will be a big loss for us.
"But there's experience to come in with James Hook and we may look at Gavin Henson in that position too."
Flanker Lydiate is a doubt for the clash at Lansdowne Road because of an ankle problem, but the prognosis over centre Roberts' knee injury is more positive.
"Dan Lydiate is touch and go. We're hoping Jamie Roberts will be OK," said Gatland.
Wales have been installed as second favourites to win the Six Nations on the strength of their heroics at the World Cup.
A 9-8 defeat by France prevented them from reaching the final by the narrowest of margins as they exceeded all expectations in New Zealand.
Captain Sam Warburton believes the key to a successful Six Nations is adopting the same fearless approach that served them so well at the World Cup, though he admits that may be difficult.
"It was a missed opportunity in New Zealand because we missed out on getting to the final by one point," said Warburton.
"Maybe we were a little bit naive out there in that we didn't realise how big a stage we were playing on.
"We played each game as just another rugby match. We played with no fear and never went into our shells.
"That will probably be the same message this time - don't think too much about it and ignore all the stuff that