Daniel Sturridge has been ruled out of England's Euro 2016 qualifier with Lithuania on Friday with a hip injury.
The Liverpool striker, 25, also misses the friendly against Italy in Turin on Tuesday, 31 March.
Sturridge sustained the problem during Liverpool's 2-1 Premier League defeat by Manchester United on Sunday.
His absence could pave the way for Tottenham's Harry Kane to make his debut at Wembley for the Group E leaders.
Sturridge's Liverpool team-mate Adam Lallana is out of the England squad after suffering a groin injury against Louis van Gaal's side and has been replaced by the uncapped Ryan Mason.
Sturridge had been hoping to make his first England appearance since September when he played in the 1-0 friendly victory over Norway.
Since then, injury has forced him to miss all of England's Euro 2016 qualifiers - against Switzerland, San Marino, Estonia and Slovenia - as well as the friendly against Scotland.
The England medical team took the decision to rule him out on Monday evening, having assessed the striker following the squad's arrival at St. George's Park earlier in the day.
Sturridge scored the hosts' consolation against Manchester United at Anfield, but afterwards complained of discomfort in his hip.
Uncapped Kane, captain Wayne Rooney and Arsenal's Danny Welbeck are alternative forward options.
England lead qualifying Group E by six points thanks to a 100% record in their first four games.
The top two countries qualify automatically for the finals in France next summer.
Goalkeepers: Joe Hart (Manchester City), Rob Green (Queens Park Rangers), Jack Butland (Stoke City).
Defenders: Leighton Baines (Everton), Gary Cahill (Chelsea), Nathaniel Clyne (Southampton), Kieran Gibbs (Arsenal), Phil Jagielka (Everton), Phil Jones (Manchester United), Danny Rose (Tottenham Hotspur), Chris Smalling (Manchester United), Kyle Walker (Tottenham Hotspur).
Midfielders: Ross Barkley (Everton), Michael Carrick (Manchester United), Fabian Delph (Aston Villa), Jordan Henderson (Liverpool), Ryan Mason (Tottenham), James Milner (Manchester City), Raheem Sterling (Liverpool), Andros Townsend (Tottenham Hotspur), Theo Walcott (Arsenal).
Forwards: Harry Kane (Tottenham Hotspur), Wayne Rooney (Manchester United), Danny Welbeck (Arsenal).