England winger Mark Cueto has been ruled out of the opening Six Nations match against Scotland on 3 February because of a calf injury.
Cueto has won 18 caps for England
The Sale winger joins Paul Sackey on the sidelines, while England coach Brian Ashton has dropped scrum-half Shaun Perry and lock Alex Brown.
Former rugby league star Andy Farrell could make his Test debut in union, while Jonny Wilkinson is also retained.
Ashton will name his team for the Twickenham match on Monday.
"The medical opinion was that Paul and Mark would not be fit and I wish them all the best for a speedy recovery," said Ashton.
"Shaun and Alex have just missed the cut. It was a very tough decision and underlines the strong competition for places."
Perry and Brown will join the England Saxons squad for the match against Italy A on 2 February.
Ellis has not played for England since March 2006
The omission of Perry, who has been suffering with a rib injury, appears to open the door to a Test recall for Leicester scrum-half Harry Ellis after he fell out of favour under previous coach Andy Robinson.
Ellis and Gloucester's Peter Richards are the two scrum-halves left in the 29-man squad, with Ellis the favourite to start.
Sackey has a knee injury, and could be forced to miss England's first three matches of the tournament.
With Sackey and Cueto unavailable, the competition at full-back and wing is greatly reduced with Iain Balshaw and Josh Lewsey the only two fully-fit specialists in the squad.
Jason Robinson remains in the picture but the 32-year-old has been struggling with a neck injury, raising the prospect of Newcastle's Mathew Tait playing on the wing or even at full-back.
Tait played at number 15 for the Falcons last week against Petrarca in the European Challenge Cup.
The inclusion of Farrell raises the possibility of the former Great Britain rugby league captain making his Test bow in his new code after impressing in recent weeks for Saracens.
And Wilkinson is also still in the squad, despite not having played in 12 weeks because of injury.
The fly-half could return for Newcastle against Leicester on Saturday.
England squad to face Scotland:
Iain Balshaw (Gloucester), Mike Catt (London Irish), Harry Ellis (Leicester Tigers), Andy Farrell (Saracens), Toby Flood (Newcastle), Shane Geraghty (London Irish), Josh Lewsey (Wasps), Jamie Noon (Newcastle), Peter Richards (Gloucester), Jason Robinson (Sale), Mathew Tait (Newcastle), Mike Tindall (Gloucester), Jonny Wilkinson (Newcastle); George Chuter (Leicester), Martin Corry (Leicester), Louis Deacon (Leicester), Perry Freshwater (Perpignan), Danny Grewcock (Bath), Magnus Lund (Sale), Lee Mears (Bath), Lewis Moody (Leicester), Tom Palmer (Wasps), Tim Payne (Wasps), Tom Rees (Wasps), Steve Thompson (Northampton), Phil Vickery (capt, Wasps), Dan Ward-Smith (Bristol), Julian White (Leicester), Joe Worsley (Wasps).