A Mexican club have won the competition that covers North America, Central America and the Caribbean for the past nine years, with Cruz Azul the reigning champions.
Seven of those titles were fought out in all-Mexican finals too, with the last club not to hail from the country to win the title being Deportivo Saprissa of Costa Rica in 2005 - when it was known as the Champions Cup.
Cruz Azul open their title defence against Costa Rican side Alajuelense on Tuesday, but Luis Fernando Tena's men have won just one of their past 10 in all competitions.
The fixture at Ciudad de Mexico will be the first between the two clubs since 1972.
Making up Group 6 is Panamanian club Chorrillo.
Other Liga MX sides starting their campaigns this week include Leon, who are away at El Salvadorian side Isidro Metapan on Tuesday.
On Wednesday, four-time winners Pachuca host Honduran outfit Real Espana.
Tuesday will see another three matches open the tournament, with MLS side Montreal Impact hosting El Salvador's FAS.
Guyana side Alpha United make their group-stage bow at home to Honduras team Olimpia, while Real Esteli - of Nicaragua - welcome Deportivo Saprissa.
On Thursday, Guatemalan club Comunicaciones will tackle Puerto Rican team Bayamon FC, before Jamaican outfit Waterhouse are on the road at Panamanian side Tauro.
