Frank Lampard is to undergo a hernia operation and will miss England's upcoming Euro 2012 qualifiers, while Peter Crouch and Bobby Zamora are doubtful.
John Terry has also added to Fabio Capello's selection woes by being ruled out of international action.
Lampard had to be replaced in the second half of Chelsea's 2-0 victory over Stoke on Saturday and is now heading for surgery on Tuesday or Wednesday.
Capello has already been notified of the situation and will not be able to call on the experienced midfielder for the clashes with Bulgaria and Switzerland.
Lampard is expected to be sidelined for a fortnight so Carlo Ancelotti could have him available for Chelsea's next Premier League game against West Ham.
Blues manager 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."
Chelsea have also confirmed that club captain, and former national team skipper, John Terry is also set to sit out the upcoming Euro 2012 qualifiers with a hamstring complaint.
A statement released on the club's official website read: "John Terry has tonight (Saturday) been ruled out of England's next two games due to injuries to his right hamstring and glute muscles.
"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."
Crouch could miss out as well after suffering a rib injury in Tottenham's surprise defeat against Wigan.
Harry Redknapp said: "I think he 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."
Zamora was watched by Capello as he opened the scoring for Fulham at Blackpool, before going off in the second half with a thigh injury.
Fulham manager Mark Hughes said: "Bobby went really stiff at half-time. He thought it was just a bang on the muscle and went out again. But he could not shake it off.
"I think he must be a doubt (for England) unfortunately. He was really looking forward to getting a chance.
"I will imagine he will go and be assessed by the England medical team and we will receive the information as quickly as we can. But at the moment he looks doubtful."
Goalkeeper David Stockdale, who is believed to be a candidate for England, is also likely to ruled out.
Hughes explained: "David has come in and done really well. But he has gone over on his ankle. He has got to be a doubt. It will be a real shame if he cannot stay with the group if he is picked."