Sir Alex Ferguson has confirmed Rio Ferdinand and Jonny Evans will both miss Saturday's Manchester derby at Old Trafford.
It means Chris Smalling will partner Nemanja Vidic in central defence for the visit of title challengers Manchester City.
Ferdinand has failed to recover from the calf injury he sustained in the warm-up before last weekend's first Premier League defeat of the season at Wolves.
The England captain is expected to be sidelined for a couple of weeks with the problem meaning he could miss the UEFA Champions League clash with Marseille later this month.
Evans has been ruled with an ankle injury that forced him to miss Northern Ireland's midweek defeat to Scotland.
"Rio Ferdinand got a calf injury last week. He will be out for a couple of weeks," said Ferguson.
"Jonny Evans was injured in training with Northern Ireland. He is out so Chris Smalling will play. I am sure he will do well."
Ferguson insists Ferdinand's latest setback is not a serious injury.
"It could have happened at any time," said Ferguson.
"It is not as if it is anything to do with his back. That was our main concern last year but his back has been fine.
"You have to remember Rio has been in first-team football since he was 17. It is a long time. He will pick up little strains, like a lot of players do.
"This is not a long-term thing. It is a couple of weeks."
Ferguson has backed Smalling to back the void left by Ferdinand's absence and is confident the England Under 21 international can handle the derby clash.
"Chris has made excellent progress this season," said Ferguson.
"He got a bit of tightness in his back last Friday, which is why I used Jonny Evans as a substitute last week.
"We are very pleased with him. He has been outstanding since he came to the club.
"He has played a few games now. Of course, he lacks that big-game experience but in terms of the experience he has had, he has used it well and he has done well."