Chelsea have confirmed that Ashley Cole will be unavailable for out for three months after fracturing his left ankle on Wednesday.
The left-back sustained the injury in the Blues' 2-1 defeat to Everton at Goodison Park in a challenge with Landon Donovan.
England's first game in the finals is against a USA side which is expected to feature Donovan.
Cole will now be in a race against time to be fit for Premier League title-chasing Chelsea's last game of the season against Wigan on 9th May.
Chelsea boss Carlo Ancelotti said he "did not know" if Cole would recover in time to play in South Africa.
The injury raises the prospect of Manchester City's Wayne Bridge playing alongside John Terry for England.
Terry is alleged to have had an affair with Bridge's ex-girlfriend Vanessa Perroncel, and Bridge has not yet indicated whether he is prepared to play alongside his former Chelsea team-mate for England.
Ancelotti told Sky Sports News: "We are very disappointed because Ashley is a very important player for us. Now we have to do our best to help him recover quickly."
Asked about the former Arsenal player's chances of making the finals, he said: "I don't know. I think so. I hope for him and for the England team."
England coach Fabio Capello said: "It's bad news for me because he is an important player. Ashley is very good when we defend and good going forward. He is really dangerous and I hope this problem will be not so bad."
Russia international Yuri Zhirkov will be Cole's likely replacement at club level for the remainder of the season.
The Italian said: "Yuri Zhirkov is a fantastic full-back so we can use him in this moment."