Brian O'Driscoll and hooker Rory Best have been ruled out of the forthcoming autumn international series for Ireland because of injuries.
O'Driscoll picked up an ankle injury in Leinster's game with Cardiff Blues and scans have shown that he will require surgery to repair ligament damage.
The inspirational centre is set to be out of action for eight to 12 weeks.
Best sustained sprained ligaments in his neck while playing for Ulster and will require rest and rehabilitation.
The former Ulster captain suffered the injury in his province's Pro12 win over the Dragons and his situation wil be assessed again after a period of four to six weeks.
Uncapped Richardt Strauss and Sean Cronin, who has 21 caps, are now set to battle it out for the number two shirt.
Strauss, born and raised in South Africa but uncapped by the Springboks, qualifies for Ireland on residency grounds this month having represented Leinster since 2009.
Rob Kearney has been ruled out of the series with a back injury
Cronin was one of seven players added to the original Irish panel of 31 on Sunday after Irish management reported that several of the squad had suffered knocks while in action for their clubs.
Ulster quartet Craig Gilroy, Paul Marshall, Paddy Jackson and Declan Fitzpatrick were all called up, along with Michael Bent and Tiernan O'Halloran.
News of the absence of two of Ireland's most senior and experienced players will come as a further blow to coach Declan Kidney, who already had to plan without ERC player of the year Rob Kearney because of a back injury.
Keith Earls was a candidate to replace Kearney, but O'Driscoll's absence is likely to see him moved to outside centre.
That leaves winger Tommy Bowe or Felix Jones, who is short of game time after recently returning from injury, as the options for the number 15 jersey.
Paul O'Connell will take the captaincy and it will be hoped he avoids injury given Best is third choice for the leadership duties.
O'Driscoll's injury will also see him miss Leinster's Heineken Cup games in December, and the Lions star may even face a race against time to make the start of Ireland's Six Nations campaign in February.
Best must be rated doubtful for Ulster's crucial Heineken Cup double-header against Northampton on 7 and 15 December.
Ireland begin their autumn series against South Africa in Dublin on 10 November, followed by a game between an Ireland XV and Fiji at Thomond Park a week later.
Argentina visit the Aviva Stadium on 24 November.
Ireland squad: Michael Bent (Leinster), Tommy Bowe (Ulster), Darren Cave (Ulster), Tom Court (Ulster), Sean Cronin (Leinster), Gordon D'Arcy (Leinster), Keith Earls (Munster), Stephen Ferris (Ulster), Declan Fitzpatrick (Ulster), Craig Gilroy (Ulster), Cian Healy (Leinster), Jamie Heaslip (Leinster), Iain Henderson (Ulster), Chris Henry (Ulster), Paddy Jackson (Ulster), David Kilcoyne (Munster), Luke Marshall (Ulster), Paul Marshall (Ulster), John Muldoon (Connacht), Conor Murray (Munster), Mike McCarthy (Connacht), Fergus McFadden (Leinster), Kevin McLaughlin (Leinster), Donncha O'Callaghan (Munster), Paul O'Connell (Munster), Tiernan O'Halloran (Connacht), Ronan O'Gara (Munster), Peter O'Mahony (Munster), Eoin Reddan (Leinster), Mike Ross (Leinster), Donnacha Ryan (Munster), Jonathan Sexton (Leinster), Richardt Strauss (Leinster), Andrew Trimble (Ulster), Dan Tuohy (Ulster), Simon Zebo (Munster).