Ireland captain Brian O'Driscoll and hooker Rory Best have been ruled out of the Guinness Series.
O'Driscoll picked up an ankle injury in Leinster's game against the Cardiff Blues and following further scans and specialist review by the Ireland medical team, it has been decided that the injury will require surgery to repair ligament damage.
The veteran international centre will miss the visit of South Africa, Fiji and Argentina next month but should be fit to lead his country in the 2013 Six Nations Championship after eight to 12 weeks of rehabilitation.
O'Driscoll's setback is another huge blow to Heineken champions Leinster's hopes of claiming three European Cups in a row, particulary with fellow provincial and national colleague Rob Kearney out for 10 weeks due to a back injury.
Ulster hooker Best joins O'Driscoll on the sidelines due to a neck injury he sustained playing in the Rabodirect Pro12 game in Wales 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 four to six weeks before a further assessment of the injury.
Munster's Keith Earls is now likely to replace O'Driscoll at outside centre with either Earls' provincial colleague Felix Jones, who is short of game time after recently returning from injury, or Tommy Bowe of Ulster as the options for the number 15 jersey; Lions skipper Paul O'Connell will take the captaincy.