Chelsea duo John Terry and Frank Lampard both pulled out on Saturday night.
The news was confirmed by the Stamford Bridge side following the club's 2-0 victory over Stoke.
At a time when Capello is desperate for two positive results to relieve the pressure that built up after England's dismal World Cup performances, it is something the Italian could have done without.
Having discarded Matthew Upson and with Ledley King and Jamie Carragher back in the international wilderness, it means Capello will not have any of the central defenders from the World Cup.
Since then, Manchester United's Wes Brown has also announced his retirement.
Phil Jagielka and Michael Dawson both featured in the friendly win over Hungary earlier this month but they lack experience at the highest level, while Bolton's Gary Cahill is yet to make an appearance for his country either.
In Lampard's case, Capello does have the option of pulling skipper Steven Gerrard back into a more orthodox central midfield role, although it will be interesting to see whether a renewed attempt is made to talk Paul Scholes out of retirement or pull Jack Wilshere in from the Under-21 squad.
The youngster's presence there has attracted controversy anyway, with Arsene Wenger questioning why the teenager was dumped back from the senior squad after making a pleasing debut against the Hungarians.
"John Terry has tonight been ruled out of England's next two games due to injuries to his right hamstring and glute muscles," said a statement on the Chelsea website.
"John has spoken personally to the England management team, and Chelsea and England medical staff have also been in touch. All are agreed that John's injuries, that he has carried since pre-season, would benefit from a period of rest and rehabilitation."
Lampard limped off in the second half of Saturday afternoon's clash, when he missed a penalty, and will undergo a hernia operation which will sideline him for around a fortnight.
Chelsea manager Carlo Ancelotti said: "It is a very easy surgery but he has started to feel pain and he needs to have the operation. We have already spoken with the national team to explain the situation."
In addition to the loss of Terry and Lampard, there are major doubts over strikers Bobby Zamora, who made his debut against Hungary but limped out of Fulham's 2-2 draw at Blackpool, and Spurs pair Peter Crouch and Jermain Defoe, who were both tipped for a recall.
Spurs boss Harry Redknapp fears Crouch may have broken a rib in the shock defeat to Wigan this afternoon, while Defoe has a long-standing groin complaint.
"I think he (Crouch) might have done a rib; he was in agony at half-time.
"He's not sure if he's broken a rib or what he did but he was in pain.
"I'm not sure about Jermain - only because I haven't asked him - whether he had any reaction from the groin or whether he needs an op or not."
If that was not bad enough, Fulham keeper David Stockdale, who was expected to be selected as back-up to Joe Hart and Ben Foster, is also a likely absentee after getting a knock at Blackpool on Saturday afternoon, one of three matches attended by Capello.
The Italian also saw Arsenal win at Blackburn and Manchester United's victory over West Ham, when Scholes and Scott Parker also caught the eye.
Capello is expected at Villa Park for Everton's visit to the midlands on Sunday, which offers Gabriel Agbonlahor, among others, the chance to give the England manager a nudge after missing the World Cup.
With Paul Robinson also retired, Chris Kirkland and Scott Carson both out of form and Robert Green requiring a "procedure" to ease a problem in his hip, Watford's U21 keeper Scott Loach may be required again.