Toby Flood is likely to miss the start of the Six Nations with a knee injury.
The Leicester and England fly-half, 26, will probably miss England's game against Scotland on 4 February and potentially the trip to Italy the following weekend.
Leicester director of rugby Richard Cockerill said: "He has tweaked his ligaments and is likely to be out for four to six weeks."
Flood's absence could see 31-year-old Charlie Hodgson's return to the squad.
England went to the World Cup last autumn with only two options at fly-half, Flood and Jonny Wilkinson, with Saracens scrum-half Richard Wigglesworth, who had experience of playing at 10 with Sale, their back-up option if either got injured.
But England's all-time leading scorer Wilkinson, who won 91 international caps and kicked the winning drop-goal in the 2003 World Cup final, is now out of the frame, having retired from international duty last month.
Highly-rated Saracens youngster Owen Farrell, already viewed as perhaps England's best long-term option, is a serious consideration, while Gloucester's Freddie Burns is another young contender.
But Farrell's club team-mate Hodgson, who usually wears the number 10 shirt for Sarries, could be the safest short-term option - 14 months on from his last international appearance in the 21-11 defeat against South Africa at Twickenham in November 2010.
Flood suffered ligament damage against Sale last weekend, which also rules him out of the Tigers' crucial Heineken Cup clash with Ulster on Friday week (13 January).
"He hurt his knee on Sunday and we initially thought it was just like a dead leg," added Cockerill, when speaking to the Leicester Mercury.
"But it swelled up overnight and he went to see a specialist to determine the exact nature of the injury."
Flood's Leicester team-mate Manu Tuilagi is also facing a battle to be fit for the Six Nations.
Having only recently returned from a broken cheekbone, Tuilagi limped off late on in last week's v32-13 victory against Worcester and subsequently missed the win over Sale before scans revealed that he faces another month on the sidelines.
Tigers club-mate Louis Deacon is definitely out of the tournament, the second-row forward facing four months on the sidelines with a torn hamstring.
The Leicester trio's absence is another blow for interim coach Stuart Lancaster, who has dropped Danny Care after the Harlequins scrum-half's New Year's Day arrest for drink-driving.
Lancaster is set to name his elite player squad on 11 January.