Devin Toner will miss the rest of Ireland's Six Nations campaign after undergoing ankle surgery.
The lock injured his ankle in last Saturday's defeat to England and the IRFU today confirmed that he faces a lengthy lay-off.
"Devin Toner had an ankle op, he's out for about two months," said a spokesman.
Sean O'Brien didn't train with the squad in today's captain's run but will start tomorrow's clash against Scotland.
The flanker is being "managed" said the union.
Toner has been a mainstay of Joe Schmidt's side and is replaced by Quinn Roux, who will win his tenth cap.
Rory Best said: "It's a massive [blow]. He's been a big part of what we've created here over the last while and he's a great player.
"I would say over the last 18 months, two years, he's probably played some of the best rugby of his career.
"To lose a player like that and the intellectual property he brings around the lineout [is massive].
"You all know him, just the calmness that he has is a great thing to have around the team environment so he'll be a loss as any great player is but when these things happen it gives an opportunity to somebody else.
"Quinn Roux, I thought, was great when he came on [against England] and he showed a lot of physicality.
"He's been playing very well for Connacht and this is going to be a massive opportunity for him and also a big opportunity for James Ryan to step up and also lead in that second row."
Toner joins fellow locks Iain Henderson and Tadhg Beirne on the sidelines but captain Best, who will win his 115th cap tomorrow, said that the timing could have been worse, with a World Cup coming down the road in September.
"It's better happening now and we'll see how much depth we have because we saw in the last World Cup [against Argentina in the quarter-final defeat] what a couple of injuries can do.
"We need to make sure that the layer below that [is ready], even if you look at Ultan Dillane on the bench, when called upon for Ireland he has been fantastic.
"To lose three world class players in one position is difficult but what an opportunity for the two boys to come in and show what they are about, and say, 'yeah, we've lost three world class players but we've actually opened our eyes to two that were right there as well and what depth we'll have then, we'll not just have four but we'll have six."
