France prop Pieter de Villiers will miss the Test match against Australia on November 13 after injuring his left thigh.
The injury is a further blow for the Stade Francais player who has just recovered from a finger injury which has kept him out of action for the past four weeks.
France coach Bernard Laporte is due to announce his team for their clash with the Wallabies at the Stade de France and De Villiers has accepted he will not be a part of it after the doctors advised him to rest for up to 10 days.
"This is very frustrating, I think it will be too short a time to get fit for the French team," said De Villiers in L'Equipe.
"I think I need to resume competition with Top 16 matches to reassure my Stade Francais coach and then Laporte."
Meanwhile, France team manager Jo Maso has confirmed they will have to find a replacement for De Villiers.
"Pieter has been a key element in our squad for four years and even if we knew he would not play against Cardiff (in the European cup) and that he had only played one match this campaign we had received guarantees from his club," said Maso.
"We were planning to take him in the 22-man squad against Australia but now we must find someone else."
However, Laporte is refusing to press the panic button.
"There is no room for panic," he added, "I will be in touch with the Stade Francais doctor to find out the seriousness of Pieter's injury.
"We have time before the match with Australia and this is not a problem if Pieter only played one match this season.
"He has trained well in the past four weeks. We will not take any risk but we will make the right decision at the right time."
De Villiers, who was part of last year's RBS 6 Nations success, missed out on the 2003 event.
He was then forced to pull out of the 2003 World Cup in Australia after injuring his shoulder a few weeks before the start.