Bubbling Mexico face in-form Honduras
Honduras lead from the United States on goal difference with Mexico in third place, level on points with Costa Rica with three rounds of games remaining.
El Salvador and Trinidad and Tobago are bottom on five points each and while they are not mathematically out of the reckoning, that could change after Wednesday's games.
Trinidad are at home to the United States and El Salvador host a Costa Rica team smarting from Saturday's 3-0 home defeat to Mexico.
The top three teams from the North, Central America and Caribbean region qualify automatically for next year's finals in South Africa with the fourth-placed side going into a playoff against South America's fifth best.
Inspired by a brilliant individual performance from Giovani Dos Santos, Mexico produced their best display yet in qualifying and head into the clash at the Azteca in rich form, unbeaten in 11 games.
Coach Javier Aguirre will again be without captain and central defensive mainstay Rafael Marquez and forward Carlos Vela who are injured but with Dos Santos on fire and the passionate Azteca crowd behind them, the Mexicans fancy their chances.
"The team is working well but we face a tough test against a very good Honduran team and we need to show how we play at home," Dos Santos told reporters.
Honduras are not lacking in confidence, though, after crushing Trinidad 4-1 with striker Carlos Pavon showing his scoring touch with a first-half double.
With Carlos Costly back from suspension and David Suazo fit again, Reinaldo Rueda has plenty of options in attack but will know his midfield need to disrupt Mexico's rhythm.
The U.S, who laboured to come from behind and beat El Salvador 2-1 on Saturday, need to pick up three points in Port of Spain against Trinidad and are boosted by the return from suspension of AC Milan defender Oguchi Onyewu.
Bob Bradley's side must travel to Honduras in October before finishing up against Costa Rica in Washington.