Jonathan Davies and Rhys Patchell both need surgery after sustaining injuries at the Rugby World Cup and face lengthy spells on the sidelines.
The Welsh Rugby Union announced the news in a statement, with Davies set to be out for more than six months because of a left knee injury suffered against Fiji.
The centre missed the quarter-final against France but returned for the semi-final against South Africa and the third-place play-off against New Zealand, playing the full 80 minutes on both occasions.
However, he wore heavy strapping and it has now been revealed that the injury he sustained is a serious one.
Fly-half Patchell suffered his shoulder injury against the All Blacks and is touch and go for the Six Nations, with his recovery time estimated to be between 12 and 16 weeks.
Wales play their first match against Italy on 1 February, with their final clash on March 14 against Scotland in Cardiff.
Wales were without first-choice fly-half, Gareth Anscombe, for the entirety of the World Cup after he suffered a serious knee injury, and he will also miss the Six Nations.