Wayne Rooney could be sidelined for two or three weeks after tearing a ligament in his knee.
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The striker missed Manchester United's 4-3 win over Newcastle as an injury-hit team came from behind to go seven points clear at the top of the Premier League.
And Sir Alex Ferguson said United might be without Rooney until the middle of January.
He told MUTV: "Wayne had a volley yesterday towards the end of training and he's torn the ligament in the back of his knee."
Ferguson admitted Rooney had been below his best in Sunday's 1-1 draw at Swansea and had expected a reaction from the striker against Newcastle.
He explained: "He could be out for two or three weeks which is unfortunate because I thought after his performance on Sunday he could be brilliant, you know you don't have two performances like Wayne did on Sunday. He was desperate to play and unfortunately couldn't risk him."
United now have a lengthy injury list with Ashley Young, Phil Jones and Danny Welbeck also sitting out the seven-goal thriller at Old Trafford.
Ferguson said: "Danny Welbeck took ill in the team hotel yesterday [Tuesday] and Ashley Young got injured in training also. Phil Jones got his injury last week against Swansea."
Captain Nemanja Vidic was an unused substitute after making his first start for three months at the Liberty Stadium.
Ferguson explained: "We couldn't risk Vida after his first game at Swansea, he had some soreness in his knee after being out for so long which is to be expected."