Last year's Copa Libertadores runners-up Penarol were thrashed 4-0 at home by Colombia's Atletico Nacional on Tuesday, leaving the Uruguayan club in early trouble in this year's competition with no points from two games.
Jherson Cordoba and Dorlan Pabon both scored twice for Atletico Nacional, which moves to the top of Group 8 with a perfect record from its two games.
In other group stage matches on Tuesday: Mexico's Cruz Azul won 4-0 against Venezuela's Deportivo Tachira, Argentina's Arsenal defeated Venezuela's Zamora 3-0 and Bolivar, of Bolivia, lost 3-1 against Chile's Union Espanola.
In Group 8, Cordoba opened the scoring for Atletico Nacional in the 21st minute, and added the second from close range four minutes after halftime.
Pabon broke free from the defense and slotted the ball into the corner of the net in the 65th to shore up the victory, and added the fourth goal for his team in the 78th, with a strike from the edge of the penalty area.
The other teams in Group 8, Universidad de Chile and Argentina's Godoy Cruz, play their second game of the group stage on Wednesday.
In Mexico City in Group 6, Cruz Azul, unbeaten in seven matches in the Mexican league, made it two wins in its first two games in the Copa Libertadores, with Adrian Cortes converting a penalty in the 19th minute.
Colombian Edixon Perea made it 2-0 with a left foot shot in the 56th, Javier Orozco tapped in the third in the 79th and, two minutes later, Argentine Emanuel Villa completed the scoring.
Deportivo Tachira remains on one point, with the other Group 8 teams, Brazil's Corinthians and Paraguay's Nacional, playing in two weeks.
In Sarandi, Argentina, three first half goals gave Arsenal the win against Zamora in Group 4.
A shot from 20 yards (meters) from Jorge Ortiz in the 2nd minute took a big deflection off a defender and although the goalkeeper got a hand to it, he couldn't stop it going into the net.
Colombian Carlos Carbonero added the second 15 minutes later, and Luciano Leguizamon made it 3-0 two minutes before halftime.
In Group 4, Arsenal now has three points, as does Brazil's Fluminense, with Boca Juniors and Zamora on one point. Boca and Fluminense play their second group game on March 7.
In La Paz in Tuesday's Group 3 game, Union Espanola scored three goals in the last 30 minutes to come from behind from a 1st minute goal by Bolivar's Edhemir Rodriguez.
Mauro Diaz, Emanuel Herrera and Jean Paul Pineda got the goals for the Chilean team.
The result improves Union Espanola to six points from its first two games, with Bolivar remaining on one point. Chile's Universidad Catolica and Colombia's Atletico Junior, the other teams in Group 3, play each other on Thursday.
Group stage games continue this week with two games on Wednesday and three games on Thursday.
