The top two finishers in each group advance to the six-team, home-and-home final round. The top three finishers in the final-round group qualify for South Africa 2010 and the fourth-place finisher plays off with South America's No. 5 team for what could be Concacaf's fourth spot.
If the USA, which downed Barbados in a home-and-home series to advance to the semifinal round, earns a spot in South Africa it will have played 18 qualifying games.
The USA is the favorite by a longshot, but it begins with two games on road: Wednesday vs. Guatemala and Sept. 6 vs. Cuba. A win against Guatemala, which always plays the Americans tough at home, would put them on a smooth course to advancing to the final round. Guatemala is led by MLS star Carlos Ruiz.
Trinidad & Tobago, aiming for a second straight World Cup appearance, travels to Cuba on Wednesday. The Cubans have prepared with a 15-game tour of Germany, from where its coach, Reinhold Fanz hails.
Former England coach Sven Goran Eriksson makes his debut in official competition as Mexico's coach when El Tri hosts Honduras at Azteca Stadium. Eriksson has called in 12 foreign-based players, including the Chicago Fire's Cuauhtemoc Blanco.
In their last meeting, Honduras upset Mexico, 2-1, at the 2007 Gold Cup.
Mexico and Honduras last met in World Cup qualifying in the 2002 campaign, when El Tri won, 3-0, at home but lost 3-1 in San Pedro Sula in what is considered one of Mexico's worst defeats.
Honduras' squad, which features Inter Milan's David Suazo, may be the strongest in its history.
Canada, led by Houston Dynamo playmaker Dwayne De Rosario, faces Jamaica, which has welcomed back Coach Rene Simoes, who guided the Reggae Boyz to their only World Cup appearance, in 1998.
The only two Central American teams to have reached the World Cup more than once meet on Wednesday when Costa Rica (1990, 2002, 2006) hosts El Salvador (1970, 1986).
El Salvador is coached by Mexican Carlos de los Cobos while Costa Rica, which has been in poor form, replaced Hernan Medford in June with Rodrigo Kenton.
In the other Group C opener, with Haiti hosts Suriname, which fields several players from the Dutch league.