Injury-hit Ireland suffered another setback ahead of their clash with South Africa when Paul O'Connell was ruled out of Saturday's match at Dublin's Lansdowne Road with a back problem.
Officials had hoped the veteran lock's injury was easing after seeing O'Connell train with the Ireland squad earlier this week.
But an Irish Rugby Football Union (IRFU) statement issued Wednesday said the 33-year-old O'Connell, in line to have won his 86th Ireland cap this weekend, was unfit.
"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," it read.
"Paul will see a specialist in the coming days and an update will be issued in due course."
The absence of O'Connell for the opening match of Ireland's November campaign came after Brian O'Driscoll, Sean O'Brien, Rob Kearney and Rory Best had all been ruled out of the whole series, which includes next week's non-cap match with Fiji and a Test against Argentina on November 24.
Meanwhile back-row forward Stephen Ferris is, at best, expected to feature only in the Argentina match because of an ankle injury.
As well as needing to find a new lock in the absence of O'Connell, the British and Irish Lions captain on the 2009 tour of South Africa, Ireland coach Declan Kidney must now also find a new skipper given O'Driscoll and Best are sidelined as well.
Kidney is due to name his side to play South Africa on Thursday, with the captaincy set to go to either No 8 Jamie Heaslip or fly-half Jonathan Sexton.