England flanker Chris Robshaw will miss the RBS 6 Nations after being ruled out for three months due to shoulder surgery.
The 30-year-old Harlequins player suffered the injury to his left shoulder in the 24-17 defeat at Worcester on New Year's Day, and is to undergo surgery on Monday.
Quins announced Robshaw was "expected to be out of competitive action for around 12 weeks", sidelining him for the entire Six Nations campaign in the latest blow for England head coach Eddie Jones.
Ireland host England in the final round on 18 March.
Joe Marler, Mako Vunipola and James Haskell all remain injury doubts, while Billy Vunipola will miss the early rounds and captain Dylan Hartley will be short of match action after his six-week suspension.
"Chris Robshaw will undergo surgery on his left shoulder today to repair an injury sustained in the match against Worcester Warriors on New Year's Day," the Harlequins statement added.
"Harlequins will provide relevant updates on his progress as appropriate."
Robshaw forged himself a new lease of Test-match life as England romped to a perfect 13 wins in 2016 under new boss Jones.
The 55-cap flanker relinquished the captaincy after England's failure at the 2015 World Cup, but has fought his way firmly into Jones' starting line-up.
England will open their Six Nations title defence by hosting France at Twickenham on Saturday, February 4 - and must now do without linchpin duo Robshaw and Saracens number eight Billy Vunipola.
Jones will be forced into a major back-row reshuffle, and might also be without Wasps flanker Haskell.
Haskell lasted just 35 seconds of his comeback after toe surgery in Wasps' 22-16 victory over Leicester on Sunday, suffering a concussion on tackling Freddie Burns.
Wasps boss Dai Young insisted Haskell was "totally fine" after the Ricoh Arena match, but the 31-year-old must now undergo concussion testing before being cleared for a return to action.
Harlequins prop Marler has been struggling with a calf problem, while Mako Vunipola is still recovering from a knee issue.
Saracens lock George Kruis has a minor cheekbone fracture, but has already targeted a return to action in the European Champions Cup clash with Toulon on January 21.
Wasps lock Joe Launchbury is carrying a calf issue but that is understood to be far less problematic than first feared.
Captain Hartley will be available for the opening clash against France, but will only just have served his six-week ban for striking Leinster's Sean O'Brien.
Jones must therefore weigh up whether the Northampton hooker will be match-hardened enough to feature against France.
Listen to live coverage of Leinster vs Montpellier in the Champions Cup on RTÉ 2fm's Game On from 7pm this Friday