Manchester United may be without last season's first-choice back four for their next two games, against Tottenham Hotspur and Arsenal.
Patrice Evra, the left-back, missed Sunday's 2-1 victory over West Bromwich Albion with a knee injury, the right-back, Rafael, dislocated a shoulder before the match, and then the centre-backs Rio Ferdinand and Nemanja Vidic both limped off.
United announced before the match that Brazilian Rafael will be out for the next 10 weeks after hurting his shoulder in training.
The Premier League champions' defensive problems deepened once the match was underway, with their two experienced central defenders forced off with injuries in the second half.
Vidic struggled for most of the game with a knee injury before coming off in the 52nd minute and is expected to be out for at least two weeks.
Ferdinand faces a longer spell on the sidelines with a hamstring injury which forced him off 15 minutes from time and is expected to be out for six weeks, ruling him out of England's Euro 2012 qualifiers against Wales and Bulgaria next month.
Speaking afterwards, manager Sir Alex Ferguson told Sky Sports: "We've had a rough time with injuries. Young Rafa has done his shoulder in training … and will be out for 10 weeks. He's probably going to have an operation.
"Rio will be out for six weeks. Vida will have checks on Monday, we don't know if it's just a nerve or something, but he could be out for a couple of weeks."
Evra may recover in time for Monday's opening home game of the season against Tottenham, but his three teammates, who formed United's back line for the majority of 2010/11, will be out.
A bigger worry for Ferguson is that Vidic, the United captain, will not be back in time to travel to title rivals Arsenal the following Sunday.
United said Chris Smalling, the England international, will fill at right-back while Rafael's twin brother, Fabio, started on the left against West Brom.
With the experienced duo John O'Shea and Wes Brown having moved to Sunderland in the summer, it means Ferguson is down to the bare bones defensively already.
Johnny Evans and Phil Jones, a summer signing from Blackburn Rovers, will probably play at centre-back, making the average age of United's defence just 21.