Northampton and England second row Courtney Lawes needs surgery on his ankle and will miss "the first few weeks" of the Six Nations.
Lawes, 25, has not played since 20 December because of the injury.
"This ankle has not settled down so I think he'll probably need to have a little bit of surgery," Northampton rugby director Jim Mallinder said.
England will be without number eight Ben Morgan and lock Joe Launchbury for the entire tournament through injury.
Mallinder, speaking after Northampton's 20-9 European Champions Cup victory over the Ospreys, said Lawes suffered the injury during Saints' Premiership match against east Midlands rivals Leicester just before Christmas.
England head coach Stuart Lancaster is due to name his Six Nations squad on Wednesday.
The second-row pairing in the tournament opener against Wales at the Millennium Stadium on 6 February is set to come from the trio of Dave Attwood, George Kruis and Geoff Parling, with the latter fit again having missed November's Tests because of injury.
|England Six Nations fixtures|
|6 Feb: Wales v England, 20:05 GMT|
|14 Feb: England v Italy, 14:30 GMT|
|1 Mar: Ireland v England, 15:00 GMT|
|14 Mar: England v Scotland, 17:00 GMT|
|21 Mar: England v France, 17:00 GMT|
"It is just a little bit of bone that chipped off Courtney's ankle in the Leicester game," Mallinder added. "He would be expected to get back playing while the Six Nations is still going on.
"It is a blow for us because we haven't got him for next week, and it is a blow for him and England because he is a key player."
Lawes' absence is another setback for Lancaster, who is already without Gloucester number eight Morgan for the whole of the the Six Nations after he fractured his left leg against Saracens on 9 January.
Wasps lock Launchbury, meanwhile, is out of the England reckoning because of a neck injury.