England captain Jonny Wilkinson has been ruled out for four to six weeks with a badly bruised right arm.
Wilkinson may not return to England duty until the Six Nations
The Newcastle fly-half is set to miss England's game against Canada on 13 November and appears unlikely to face South Africa and Australia.
Newcastle coach Rob Andrew said: "We have spoken to Jonny and what we are doing is in his best interests."
Wilkinson has suffered a number of setbacks since returning to action following a nine-month lay-off.
However, England coach Andy Robinson remains hopeful that Wilkinson could make a quicker than expected recovery.
"This is disappointing but we'll wait and see how Jonny responds to treatment in the next few weeks," Robinson said.
"I am not discounting him yet for next month's internationals.
22 Nov Kicks winning drop goal in World Cup final
13 Dec Ruled out for three weeks with fractured facet in shoulder
6 Feb Specialist recommends shoulder surgery, ruling Wilkinson out of Six Nations
14 May Ruled out of England tour to New Zealand
5 Sep Returns to competitive action for Newcastle
10 Oct Has treatment for dead arm during Newcastle game
11 Oct Sits out England training
21 Oct Ruled out for four to six weeks
"I discussed the problem with him last night and the most important thing is to make sure that he has time to recover properly."
After England's World Cup win in 2003, Wilkinson underwent surgery for career-threatening neck and shoulder problems, but his comeback has been blighted by a series of arm injuries.
However, Andrew insisted the haematoma in Wilkinson's upper right arm is completely unrelated to the 25-year-old's previous problems.
"This is unfortunate following on from his previous injury, but it is not related at all to that one," he said.
"We've received medical advice this week and spoken at length with Jonny, and as always we're doing what is in the best interests of the player.
"We'll just let him recover over the next few weeks and then get him back on the field again."
The fly-half's injury is a further blow for England coach Robinson, who took over from Sir Clive Woodward last week.
Robinson has already lost flanker Richard Hill, while hooker Steve Thompson is battling a rib problem and Lawrence Dallaglio has become the latest World Cup winner to retire from international rugby.
Sale Sharks' Charlie Hodgson appears to be the favourite to take over as fly-half, while Bath lock Steve
Borthwick or his club colleague, centre Mike Tindall, could captain the side.
Wilkinson's latest injury means he will also miss Newcastle's Heineken Cup opener against the Newport Gwent Dragons at Rodney Parade on Saturday.