The Chelsea man has failed to overcome a knee problem and has returned to his club in a bid to regain fitness prior to Tuesday's meeting with Poland in Warsaw.
Lampard's absence increases the likelihood of Roy Hodgson deploying Wayne Rooney in midfield, a role in which he has impressed in for Manchester United, particularly during their 3-0 win over Newcastle.
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The former Everton striker is also favourite to be named as captain due to the absence of Lampard and with Steven Gerrard suspended for the game.
Chelsea team-mate Ryan Bertrand will also join Lampard in missing the Wembley clash. The defender has been ruled out of the game through illness.
Initial reports claimed the full-back was suffering from a sore throat but he was quick to explain his absence via Twitter, saying: "Just to clarify.... Its not a 'sore throat' Im ill.swollen glands in my neck... And constant headache for 3 days now and freezin cold"