An emphatic 5-0 win in Moldova came at a cost with key defender John Terry joining his Chelsea clubmate Ashley Cole on the injury list when he was ruled out of the Ukraine game with an ankle injury, joining Wayne Rooney, Andy Carroll, Gareth Barry, Ashley Young and Scott Parker on the sidelines.
Terry, who featured in one of the pivotal moments when England beat Ukraine 1-0 in a Euro 2012 group match in Donetsk in June, picked up the knock against Moldova and limped off two minutes before the end.
Cole, who damaged his ankle in the European Super Cup against Atletico Madrid 10 days ago, missed the Moldova game but had hoped to be fit to win his 99th cap against Ukraine, but the FA's medical team sent him back to his club for treatment.
England, playing their first competitive game at Wembley under coach Roy Hodgson who is unbeaten in eight matches in charge, should build on the momentum and take another three points from Ukraine who are playing their first match of the campaign.
England have won four of the five matches played between the countries, including the last one on June 19 when Rooney scored the winner and Terry cleared a Marko Devic shot from behind the goal line, but officials failed to award a goal.
HAPPY MAN
Hodgson was a happy man after the Moldova game with youngsters like 19-year-old Alex Oxlade-Chamberlain and Tom Cleverley, 23, playing very well alongside the experienced Frank Lampard and Steven Gerrard in a flexible 4-2-3-1 formation.
Lampard, playing in a deeper role with Gerrard which allowed the youngsters room to manoeuvre, still managed to score twice, once from the spot, taking his international tally to 25, to become England's 13th highest scorer of all time.
Hodgson is expected to retain most of the starting line-up against Ukraine including Cleverley, who impressed the coach playing for Britain during the Olympic Games.
"The Games were good for him and important for me as well because that is where I sort of 'discovered' him, although of course I knew about him before," said Hodgson.
"You could call him an attacking midfielder but he's an attacking midfielder in the same way as Cesc Fabregas, he's capable of coming back and winning the ball where necessary."
Ukraine come to London facing formidable odds if they are to create an upset.
England have only ever lost two out of 40 World Cup matches (qualifiers and tournament games) at Wembley and apart from the penalty shootout defeat by Italy in the Euro quarter-finals which counts as a draw after 90 minutes, are unbeaten in 13 competitive matches.
Manager Oleg Blokhin, whose news conferences are often more entertaining than the football his side plays on the field, will be without Ukraine's greatest player, Andriy Shevchenko, who retired as a player at the end of the Euros after scoring 48 goals in 111 games for his country.
Instead, he will be relying on 22-year-old attacking midfielder Andriy Yarmolenko, the team's best player at the Euros, to orchestrate them on Tuesday along with Anatoliy Tymoschuk, who has a record 120 Ukraine caps, and the outstanding prospect Yevhen Konoplyanka.
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