Ghana hosts the 2008 tournament which runs from January 20 - February 10, with holders Egypt looking to retain their crown.
Apart from Bafana Bafana’s Aaron Mokoena and Steven Pienaar, around 38 other Premier League players could leave the domestic season in England to link up with their national team.
Portsmouth could be most affected with five of Harry Redknapp’s squad likely to be called up for national duty.
Chelsea will also be heavily burdened by the competition with four members of Avram Grant’s squad set to fly out to Ghana.
Egypt won the tournament in 2006, beating the Ivory Coast on penalties and Middlesbrough could lose Mohamed Shawky and Mido to the holders.
The exodus could spark much activity in the January transfer window with Redknapp and Grant already stating that they are likely to bring in fresh faces to cover for the players heading out to Ghana.
Only four Premier League clubs (Aston Villa, Derby County, Fulham and Manchester City) are not affected by the tournament.
The following is a list of England-based players likely to be playing in the 2008 Caf showpiece.
Arsenal - Kolo Toure and Emmanuel Eboue (Ivory Coast), Alexandre Song (Cameroon)
Birmingham - Richard Kingson (Ghana), Mehdi Nafti and Radhi Jaidi (Tunisia)
Blackburn - Aaron Mokoena (South Africa)
Bolton - El-Hadji Diouf (Senegal), Abdoulaye Meite (Ivory Coast)
Chelsea - John Obi Mikel (Nigeria), Didier Drogba and Saloman Kalou (Ivory Coast), Michael Essien (Ghana)
Everton - Joseph Yobo and Ayegbeni Yakubu (Nigeria), Steven Pienaar (South Africa)
Liverpool - Nabil El-Zhar (Morocco), Muhammed Sissoko (Mali)
Manchester United - Manucho (Angola)*
Middlesbrough - Mohamed Shawky and Mido (Egypt) Newcastle - Obafemi Martins (Nigeria), Geremi (Cameroon), Abdoulaye Faye and Habib Beye (Senegal)
Portsmouth - Papa Bouba Diop (Senegal), Nwankwo Kanu and John Utaka (Nigeria), Sulley Muntari (Ghana), Lauren (Cameroon)
Reading - Andre Bikey (Cameroon), Emerse Fae (Ivory Coast), Ibrahima Sonko (Senegal)
Sunderland - Dickson Etuhu (Nigeria)
Tottenham - Hossam Ghaly (Egypt), Didier Zokora (Ivory Coast)
West Ham United - John Pantsil (Ghana), Henri Camara (Senegal)
Wigan - Salomon Olembe (Cameroon), Julius Aghahowa (Nigeria)