Pace bowler James Anderson will be out of action for at least two months with a stress fracture in his back.
Confirmation of his injury leaves England with major problems ahead of the first Test against Sri Lanka at Lord's, which starts on 11 May.
Simon Jones suffered a knee injury in Glamorgan's C&G Trophy game on Monday and is unlikely to be considered.
Another paceman, Durham's Steve Harmison is also set to sit out the match with a shin problem.
"The parameters are that players will have to play a four-day game before the Test match," chairman of selectors David Graveney said.
"At the present stage, Harmison, (Michael) Vaughan (knee), Anderson and Jones would not be considered."
One potential replacement, Hampshire's Chris Tremlett, is also struggling after suffering an ankle problem during their Championship game against Sussex.
The selectors must now hope that Andrew Flintoff and Matthew Hoggard come through pre-Lord's appearances for their clubs unscathed.
Durham's Liam Plunkett appears likely to play his first Test on home soil but there could still be one seam bowling place to fill against Sri Lanka.
It could mean Sajid Mahmood being promoted from the one-day squad and the selectors dropped a hint when he was pulled out of the England A team to face the Sri Lankans on Thursday.
For Anderson, meanwhile, he must now concentrate on rest and recuperation after consulting a specialist in Manchester on Wednesday.
He will miss the entire Sri Lanka series and even if his recovery estimate proves accurate, it is unlikely he will be risked in the opening Test of the series which follows against Pakistan, starting on 13 July.
"It is a huge blow to Jimmy. He has worked hard and patiently at his cricket to get back into the Test and one-day environment and obviously was hoping to be involved with England right through this summer.
"But he is a fighter and he will get all the help possible at Old Trafford to overcome this setback," said Lancashire coach Mike Watkinson.
Stress fractures in the back have interrupted the careers of many fast bowlers in recent years.
New Zealand's Shane Bond, for example, was out of international cricket for over two years.
Lancashire believe Anderson's problem is nowhere near as serious.
"It is likely that he will need at least six weeks of rest and rehabilitation," said a statement on the club's website.
And he commented: "As I've already had a fortnight it means I might only have another month of the rehabilitation process.
"Obviously I'll need more time after that before I'm fit to bowl competitively again, but there are top people looking after me here at Old Trafford and I'm hoping to be back sooner than everyone first thought."
Confirmation of his injury leaves England with major problems ahead of the first Test against Sri Lanka at Lord's, which starts on 11 May.
Simon Jones suffered a knee injury in Glamorgan's C&G Trophy game on Monday and is unlikely to be considered.
Another paceman, Durham's Steve Harmison is also set to sit out the match with a shin problem.
"The parameters are that players will have to play a four-day game before the Test match," chairman of selectors David Graveney said.
"At the present stage, Harmison, (Michael) Vaughan (knee), Anderson and Jones would not be considered."
The selectors must now hope that Andrew Flintoff and Matthew Hoggard come through pre-Lord's appearances for their clubs unscathed.
Durham's Liam Plunkett appears likely to play his first Test on home soil but there could still be one seam bowling place to fill against Sri Lanka.
It could mean Sajid Mahmood being promoted from the one-day squad and the selectors dropped a hint when he was pulled out of the England A team to face the Sri Lankans on Thursday.
For Anderson, meanwhile, he must now concentrate on rest and recuperation after consulting a specialist in Manchester on Wednesday.
He will miss the entire Sri Lanka series and even if his recovery estimate proves accurate, it is unlikely he will be risked in the opening Test of the series which follows against Pakistan, starting on 13 July.
"It is a huge blow to Jimmy. He has worked hard and patiently at his cricket to get back into the Test and one-day environment and obviously was hoping to be involved with England right through this summer.
"But he is a fighter and he will get all the help possible at Old Trafford to overcome this setback," said Lancashire coach Mike Watkinson.
Stress fractures in the back have interrupted the careers of many fast bowlers in recent years.
New Zealand's Shane Bond, for example, was out of international cricket for over two years.
Lancashire believe Anderson's problem is nowhere near as serious.
"It is likely that he will need at least six weeks of rest and rehabilitation," said a statement on the club's website.
And he commented: "As I've already had a fortnight it means I might only have another month of the rehabilitation process.
"Obviously I'll need more time after that before I'm fit to bowl competitively again, but there are top people looking after me here at Old Trafford and I'm hoping to be back sooner than everyone first thought."