Nemanja Vidic has been ruled out of action for eight weeks after Manchester United confirmed he had a meniscus operation on his right knee.
Sir Alex Ferguson said on Sunday the club captain had been rested in the win against Liverpool due to him "feeling a bit tight round about his knee" before adding "Hopefully he'll be alright next week".
However the club said "further medical investigation revealed the underlying problem", exacerbating United's defensive injury crisis.
Vidic made his first appearance in eight months in August after he sustained knee ligament damage in the Champions League defeat to Basel last year.
He joins Chris Smalling, who was ruled out for 10 weeks in July after suffering a broken foot and Phil Jones, another centre-back who is recuperating after knee surgery earlier in September, on the sidelines.
That leaves Rio Ferdinand - susceptible to injuries in his 30s - and recent returnee Jonny Evans as United's only available centre-halves.
Scott Wootton and Michael Keane, two academy scholars, are Ferguson's back-up choices to Ferdinand and Evans, who started 23 games together last season.