England flanker Tom Johnson has been ruled out of the entire Six Nations with a knee ligament injury, while fly-half Freddie Burns and prop Alex Corbisiero will miss the beginning of the tournament.
Head coach Stuart Lancaster revealed the news at the tournament launch, with Exeter Chiefs back row Johnson expected to be on the sidelines for around three months.
Uncapped Worcester forward Matt Kvesic comes into the squad as cover for Johnson.
London Irish loosehead prop Corbisiero has been ruled out of England's opening two fixtures, against Scotland and Ireland, after undergoing surgery to clean out his knee.
Burns will also miss at least the Calcutta Cup clash on 2 February, with the Gloucester fly-half expected to be out for two to three weeks with knee ligament damage.
England must wait to find out if Leicester centre Manu Tuilagi will have recovered from an ankle injury in time for the opening game of the Six Nations at Twickenham.
Lancaster did confirm some positive injury news though, with full-back Alex Goode having overcome a shoulder problem that allows him to play for Saracens against Cardiff Blues in the LV= Cup this weekend.
Who will win the Six Nations?