Brian O'Driscoll will miss Ireland's entire autumn schedule after being ruled out for up to three months with an ankle injury.
The captain requires surgery after damaging a ligament while on Leinster duty against Cardiff Blues last Saturday.
In a further blow to Ireland's hopes in their Guinness Series against South Africa, Fiji and Argentina, hooker Rory Best will also be missing because of a neck injury.
Ulster front-rower Best sprained neck ligaments against the Dragons last Friday and faces up to six weeks of rehabilitation before his condition is reassessed.
But it is the news concerning inspirational leader O'Driscoll that will be most distressing to Ireland. The 33-year-old is in the final year of his contract with the Irish Rugby Football Union, with his future beyond next summer undecided.
Already stretched by the loss of Rob Kearney to a back problem, head coach Declan Kidney must re-examine his plans for the backline. 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.
Lions skipper Paul O'Connell will take the captaincy and it will be hoped he avoids injury given Best is third choice for the leadership duties.
Best's unavailability creates a chance for Leinster hooker Richardt Strauss.
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.