Wales head coach Warren Gatland has said they will be without Martyn Williams, James Hook, Dwayne Peel and Luke Charteris for this summer's campaign.
The quartet, all key players in the national set-up, will therefore miss Wales' upcoming clash against world champions South Africa and the subsequent two-Test tour of New Zealand.
Flanker Williams, who will be 35 in September, and scrum-half Peel are both being rested, while centre Hook will undergo shoulder surgery once the Ospreys complete their Magners League title push.
Meanwhile, Newport Gwent Dragons lock Charteris is currently recovering from a neck problem.
Gatland is due to name his squad on Sunday for the June 5 Springboks clash in Cardiff, which is followed by meetings with the All Blacks in Dunedin and Hamilton.
"We have some depth in these positions with the likes of Jamie Roberts, Andrew Bishop and Jonathan Davies playing well at the moment at centre," he said.
"We are okay in the second-row as well, and Sam Warburton has been pushing Martyn really hard for a back-row spot at Cardiff Blues, as well as at international level.
"South Africa in Cardiff, and then two Tests in New Zealand, means we have a tough summer ahead of us. But this is exactly the position we need to be in, and it will be perfect preparation for the World Cup."
Hook's impending surgery could sideline him for up to five months, leaving a question mark over his participation in the autumn Tests.
Despite the absences, however, Gatland is upbeat following what was a disappointing season for Wales.
"Games don't come much tougher than playing the world champion South Africans, and (Springboks coach) Peter de Villiers has a wide range of talent to choose from," he added.
"Depending on what happens in the Super 14 competition, certain players will be ruled out.
"But we will be expecting the European-based players like Butch James to figure, and (Natal) Sharks players are likely to be available, so there will be World Cup winners throughout the squad.
"They are going to be strong, but it could also be a great day for Wales. If we could win that game it would be a great platform for our summer tour.
"As for New Zealand, we just need to believe in ourselves and perform like we know we can - then, we will have a chance.
"France won a game there (New Zealand) last year and Ireland ran them close as well, so we know it can be done.
"But we are also keen to familiarise the players with our (2011) World Cup venues and training bases.
"It's not until I left New Zealand that I realised that it is such a difficult place to tour, and we want the players to have that experience, training at the same venues and staying in the same hotels as we will in 2011."