England captain Lewis Moody is likely to be sidelined for six weeks after suffering a knee ligament injury.
Moody was hurt during his club Bath's Heineken Cup victory over Italian side Aironi last Saturday, limping off during the second half, and Bath have now confirmed an injury to his medial collateral ligament.
It means the former Leicester flanker is set to miss England's opening three RBS 6 Nations games against Wales, Italy and France.
England manager Martin Johnson has already lost lock Courtney Lawes and flanker Tom Croft from his initial Six Nations plans through injuries.
Moody, 32, has won 66 England caps, and his absence will be keenly felt by Johnson.
Harlequins number eight Nick Easter would be favourite to take over as skipper.
England launch their Six Nations campaign against Wales in Cardiff on 4 February, with Lawes (knee) and Croft (shoulder) also confirmed absentees.
Bath head coach Steve Meehan said: ‘Lewis took a knock to his knee at the weekend which is slightly more serious than first thought.
‘It is frustrating for us to lose him at this stage in the season, but it does mean that other players in the squad get the opportunity to come on in his place and show us what they can do.
‘We will of course make sure he receives the best medical attention to get him back on the field as, and when, he's ready.’
England are set to name an injury replacement for Moody in their squad next Monday.
Contenders are likely to include Tom Wood, Chris Robshaw, Andy Saull and Phil Dowson, a quartet who were selected last week in the England Saxons squad.
Coach Martin Johnson said: 'It is always disappointing to lose a player and leader of Lewis' calibre. But as I have consistently said. good teams adapt to injuries, and that is what we intend to do.
'While this could still mean Lewis plays a role in the RBS 6 Nations, it does mean that another player gets the chance to step up and make it hard for him to get the shirt back.'
Johnson will announce his captain in the week leading up to the Wales game, with Moody now remaining at Bath for his rehabilitation in close consultation with the England medical team.