Coach Roy Hodgson has lost the services of central defenders Gary Cahill, Phil Jagielka, Michael Dawson and Rio Ferdinand for the opening Group H fixture and could field Manchester United midfielder Michael Carrick alongside Chris Smalling on Friday.
Even allowing for the absences of that defensive quartet, England should prove far too strong for the minnows from San Marino who have lost their last 50 international matches, scoring just seven goals and conceding over 200 and are joint-bottom of FIFA's 206 nations in the ranking table.
They are predictably bottom of the group too with no points from their opening four games, while Montenegro lead the standings with 10 points, followed by England (8), and Poland (5), although the Poles, who play second-from-bottom Ukraine, their Euro 2012 co-hosts, have a game in hand.
England are virtually certain to pick up all three points on Friday, which could take them back to the top of the table if current leaders Montenegro fail to win in Moldova, who are fourth. But the buildup to the game has been blighted by Ferdinand's withdrawal from the squad after being recalled following a 22-month absence.
Hodgson said last week he had selected the 34-year-old Manchester United defender after a series of recent outstanding performances for his club, a significant about-turn by the boss after leaving Ferdinand out of his Euro 2012 squad last summer.
However, after assurances from United manager Sir Alex Ferguson that Ferdinand would join the party, Ferdinand withdrew on Monday saying he could not break the strict training routine that he now follows.
That programme had allowed his career to flourish again after back injuries threatened to end it 18 months ago, but Hodgson could have saved himself a huge degree of media ridicule and vitriol if he had checked with Ferdinand first that he would accept his call-up, something he said he did not do when he announced his squad last Thursday.
England defeated San Marino 5-0 when the sides met at Wembley in October with two goals from Wayne Rooney, two from Danny Welbeck and a first for his country from Alex Oxlade-Chamberlain giving them an easy victory.
No matter which team Hodgson selects for Friday, the outcome should be about the same but the fixture does evoke memories of one of the unlikeliest goals in World Cup history.
The two sides first met in February 1993 with England winning their first ever meeting, a World Cup qualifer, 6-0 with at Wembley the return played in Bologna the following November in front of just 2,378 people.
That tiny crowd were stunned when San Marino shocked the visitors with a goal from David Gualtieri who scored after 8.3 seconds, regarded by FIFA as the fastest goal ever scored in a World Cup match.
England went on to win 7-1, but other group results meant they failed to qualify for the 1994 World Cup finals.
"We should have most of the possession and we should take all three points, but we will be taking nothing for granted and we will work hard for the victory while paying San Marino the ultimate respect," Hodgson told reporters.
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