Irish lose Tommy Bowe and Jamie Heaslip
The Ospreys winger and Leinster No 8 are the latest names to be added to a lengthy list of players who will miss the trip to Rome on Saturday week.
Bowe is struggling with a knee problem while Heaslip is nursing an ankle injury and the race is now on for them to return against France on 13 February.
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Hide AdIt is a significant setback to head coach Declan Kidney, who must begin the tournament without two of his most consistent performers. Heaslip was magnificent during the autumn series while Bowe has emerged as one of Ireland's most effective strike runners.
"You never like to see guys injured - we know how much playing for Ireland means to those guys," said Kidney. "We've tried to build a squad over the last few years and this will be the test of that. I have a huge belief in the way Irish rugby comes from the grass roots up."
Meanwhile, captain Brian O'Driscoll is confident Ireland can challenge for the Six Nations title if they play to their potential. He said: "Plenty of other sides did better than us (in the autumn series] but we're quietly confident that if we get our game together we'll be in the hunt in some capacity."