Tom Wood has been ruled out of England's first two RBS 6 Nations fixtures with a toe injury, the Rugby Football Union have confirmed.
The Northampton flanker will miss England's games against Scotland and Italy after being told he needs to wear a protective boot on his left foot for the next four weeks.
Wood, who had been considered a leading captaincy candidate, will still attend England's pre-Six Nations training camp in Leeds next week.
The loss of Wood is a huge blow to interim England head coach Stuart Lancaster.
Leicester trio Toby Flood, Manu Tuilagi and Louis Deacon are all sidelined through injury, at least for the Scotland and Italy games, while Northampton lock Courtney Lawes is battling to overcome a knee problem.
Wood would have been a certainty to start at Murrayfield, and his absence will cause a back-row rethink for Lancaster and his coaching staff. It could open the door for Bristol-born number eight Ben Morgan to make a Test debut, with Harlequins captain and openside flanker Chris Robshaw captaining his country.
Morgan, who plays for the Scarlets and had qualified for Wales on residency, pinned his international colours to the England mast earlier this month, and he was immediately included in Lancaster's elite player squad.
Had Wood, who made England's World Cup squad last year but was largely overlooked by then manager Martin Johnson, been fit, then the likelihood would have been Robshaw packing down at number eight alongside Wood and Leicester's Tom Croft.
Robshaw is now favourite to skipper England in Edinburgh, although Croft and hooker Dylan Hartley both offer leadership credentials.
Wood said: "There is never a good time to be injured and I'm obviously very disappointed but I'm working closely with the medics, at both Northampton Saints and England, who will be keeping a close eye on it and assessing it day by day."