Ireland flanker Ryan Baird will be out for up to three months with a leg injury and utility back Jamie Osborne will miss four months due to a shoulder problem, making both major doubts for the Six Nations.
Baird, one of Ireland's bright spots in a mixed series of Autumn tests, suffered a suspected fractured tibia in Saturday's bruising loss to South Africa, coach Andy Farrell said, and Osborne was injured against Japan this month.
The Leinster pair are also set to miss all four group games of the European Cup.
Lock Joe McCarthy, who missed all Ireland's November tests, has entered the final stages of his rehabilitation from a foot injury and will be further assessed as the week continues.
Ireland open their Six Nations at holders France on 5 February and face a trip England on 21 February.