The Chelsea midfielder has been suffering with a knee injury and the problem has forced him to return to Chelsea to aid his recovery.
However, he will link up once again with Roy Hodgson's squad on Sunday so England's doctors can ascertain his availability for Tuesday's trip to face Poland.
An FA statement read: "Frank Lampard has returned to his club for further treatment and will not be available for England's FIFA World Cup qualifier with San Marino.
"The Chelsea midfielder will return to the England squad on Sunday for assessment ahead of the away qualifier with Poland on Tuesday."
England captain Steven Gerrard is also missing against the team ranked joint worst in the world as he serves a suspension following his red card in the 1-1 draw with Ukraine last month.
There is speculation that, as well as possibly being named captain, Wayne Rooney will also be asked to play in midfield, as he has done for Manchester United in recent games.
The FA later confirmed that Lampard's Chelsea colleague, Ryan Bertrand, had also returned to the Premier League club due to illness. He will be assessed again ahead of the Poland game, but England do have Ashley Cole and Leighton Baines in the squad at left-back.
However, just a day after FA chairman David Bernstein said England players would have to follow a new code of conduct - including guidance over use of Twitter - Bertrand used an expletive when denying reports that a sore throat had forced him to withdraw from the squad.
He tweeted: "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
"Do you think a 'sorethroat' could stop me being apart of a match for my club or country? #yourf*****gnuts this is what every boy dreams of"
England currently sit second in Group H with four points in two games.
- Frank Lampard