Ireland captain Brian O'Driscoll and Ulster hooker Rory Best have both been ruled out of the November international Test matches.
Leinster's O'Driscoll picked up an ankle injury in the game against the Cardiff Blues, and following further scans and a specialist review by the Ireland medical team, it has been decided that the injury will require surgery to repair ligament damage, ruling the second centre out for eight to 12 weeks.
Best has also been ruled out of the games against South Africa, Fiji and Argentina, due to a neck injury he sustained last Friday playing in the RaboDirect PRO12 against the Dragons.
Following a scan and medical review, it was confirmed that Best has sprained ligaments in his neck, which will require a rest and rehabilitation period of between 4-6 weeks before a further assessment of the injury.
Ireland coach Declan Kidney will talk to the media at 4.30pm, possibly announcing further call ups to replace the injured duo for the Guinness Series.
Already stretched by the loss of Rob Kearney to a back problem, Kidney must now 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.