Jamie Heaslip is set to captain Ireland against South Africa at Lansdowne Road on Saturday after Paul O'Connell's latest attempt to recover from recurring injury was dashed.
Despite competing the two intensive training sessions required of him this week, after which there was reported to be no adverse reaction to the back spasms that have afflicted his season, O'Connell's dramatic withdrawal was confirmed by the IRFU yesterday.
Mystery now surrounds his availability for the rest of the November series as medics attempt to unravel the nature of the second-row's latest breakdown.
O'Connell, who underwent knee surgery at the end of last season, has only competed two 60-minute spells of rugby for Munster this term.
"O'Connell returned to training at the start of this week and took a full part in the squad sessions on Monday and Tuesday, but suffered a reaction and will not be fit for selection for this weekend's game.
"Paul will see a specialist in the coming days and an update will be issued in due course."
Declan Kidney will turn to Heaslip (right) to lead the side and is likely to draft in the experienced Donncha O'Callaghan to a team that is already bereft of key players such as Brian O'Driscoll, Rory Best, Stephen Ferris, Sean O'Brien and Rob Kearney.
O'Connell is now 33 and he has admitted his frustration at the manner in which injuries have blighted his progress in recent times.
There must now be severe doubts about his ability to return to optimum fitness in the future.
O'Callaghan's experience may be called upon by Kidney in the light of so many high-profile withdrawals as Ireland begin a series of November Tests which are crucial to their chances of remaining within the tier of second seeds -- ahead of next month's draw for the 2015 World Cup.