Alun Wyn Jones and George North will miss the next month after picking up injuries during Wales' triumphant Six Nations Grand Slam campaign, the Ospreys have confirmed.
Jones led Wales to five wins out of five in the championship and was named player of the tournament on Friday after a public vote.
North scored twice in the opening match against France, but only played nine minutes of the victory over Ireland that sealed the Grand Slam.
They have both returned to club rugby ahead of the final weeks of the Pro14 season, but the Ospreys remain unsure whether they will be able to feature in any of their four matches.
"Alun Wyn suffered knee ligament damage last weekend and is currently rehabbing," an Ospreys statement read.
"He won't travel to South Africa [to face the Cheetahs and Southern Kings] with the squad at the start of April but at this stage we haven't ruled him out of the Judgment Day game against Cardiff Blues [on April 27].
"George fractured two metacarpals in his left hand early in the Scotland match. Having seen a specialist this week, he needs time for the bones to heal but we are optimistic about the potential for him to be involved on Judgment Day."
While Jones and North have a chance of playing again this season, Scott Williams is "progressing well" towards a return ahead of the Rugby World Cup.
"Scott is recovering from the disc problem in his lower back which kept him out of the Six Nations," the Ospreys' statement continued.
"He is progressing well but we aren't expecting to see him back representing the Ospreys before the end of the season. He will continue his rehabilitation into pre-season with the goal of making himself available for the Rugby World Cup."