Frank Lampard will miss Euro 2012 after a scan revealed the extent of his thigh problem, with Jordan Henderson called up to replace him in the England squad.
Chelsea midfielder Lampard picked up a problem in training on Wednesday and medical tests have now shown that he would not be able to recover in time for the tournament in Poland and Ukraine.
The Football Association has confirmed that Lampard, who will be 34 next month, will not be part of Roy Hodgson's 23-man squad.
It is devastating news for England, who have already had to deal with the loss of one midfielder after Manchester City's Gareth Barry suffered a stomach injury in Saturday's friendly win over Norway.
And for Lampard, it potentially spells the end of his entire England career, with Hodgson expected to offer the younger midfielders a chance to prove themselves during next autumn's World Cup qualifying programme.
Lampard has nevertheless made it clear that he has no plans to quit international football, having made his England debut in 1999 and earned 90 caps in total.
Henderson will be called into the England squad providing Hodgson gets the green light from UEFA, which should be automatic as Lampard has suffered a fresh injury after Tuesday's deadline.
Hodgson said: "It's a huge blow for the team, especially coming after the loss of another senior player in Gareth Barry.
"The fact that the doctor cannot guarantee Frank could take part in any of the group matches means we have to replace him in the central midfield area.
"Apart from it being a huge blow to me and the team, I'm especially disappointed for Frank himself.
"He has been in very good form and was looking forward to the tournament.
"He made a huge contribution towards us qualifying for the Euros so it is cruel to be forced out through injury just before the tournament."
Defender Phil Jagielka was drafted into the squad in place of Barry and Lampard's injury leaves Hodgson with a lack of experienced options in central midfield.
Scott Parker, who has only just recovered from Achilles problem, is expected to start alongside captain Steven Gerrard in England's opening Group D match against France on 11th June.