Charlie Hodgson and Andrew Sheridan will miss the rest of the season after suffering knee and ankle injuries in England's win over South Africa.
Hodson was injured shortly before the break against South Africa
The Sale duo were carried off in Saturday's 23-21 victory at Twickenham.
And further analysis showed fly-half Hodgson has ruptured his cruciate knee ligament, while prop Sheridan has a broken left ankle and ligament damage.
They will both be operated on in the next week but are certain to miss England's Six Nations campaign.
Hodgson's injury ends a miserable autumn series for the Sale fly-half after he struggled to reproduce his outstanding Guinness Premiership form on the international stage.
Their absence will be a real blow to England and Sale Sharks
England head coach Andy Robinson
And with Jonny Wilkinson sidelined until the new year while he recovers from kidney damage, England's number 10 shirt is now likely to be contested by Andy Goode - Hodgson's probable replacement against South Africa again next Saturday - Toby Flood and Olly Barkley.
Hodgson's injury is a repeat of the problem he suffered, albeit in his other knee, in 2003, which ruled him out of England's World Cup campaign.
Sheridan, like Hodgson, now faces a long rehabilitation period after undergoing surgery.
Sheridan missed a large chunk of last season due to injury
England coach Andy Robinson said: "Everyone feels for Charlie and Andrew, and we wish them all the best for their recovery.
"Charlie and Andrew are key members of the squad and they have contributed massively this autumn. Their absence will be a real blow to England and Sale Sharks."
While England contemplate a Six Nations season without Hodgson and Sheridan, Sale's hopes of defending their Premiership title has taken another major hit.
They have also revealed that Scottish international flanker Jason White has been laid low by a season-ending injury.
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"This is a terrible blow for the players, for England and for Sale Sharks," said rugby director Philippe Saint-Andre.
"Our thoughts are with the players at this moment but we know that they will receive the very best treatment available to ensure that they return, for club and country, as soon as is possible.
"Of course, their loss is a blow to our aspirations to retain our title, and also to our chances in the EDF Energy and Heineken Cup competitions."