Corinthians leapfrogged Cerro Porteno into top spot in Group 8 with an impressive 2-0 win on Wednesday.
The Brazilian giants were beaten 3-2 by Cerro Porteno in the Copa Libertadores last week as they slipped a point off the pace.
However, Corinthians avenged that defeat on home soil thanks to Lucca and a Victor Mareco own goal.
Corinthians made the perfect start thanks to Lucca, who opened the scoring in the 21st-minute with a close-range finish after pouncing on Bruno Henrique's fluffed shot.
The points were virtually sealed just past the hour-mark, when Mareco looped the ball over his own goalkeeper as Corinthians ended a run of three consecutive defeats against Paraguayan opposition in the competition.
Corinthians are now two points clear of Santa Fe and Cerro Porteno after four matches.
Atletico Mineiro maintained their unbeaten run in the tournament thanks to a 3-0 win at home to Colo Colo.
Goals from Juan Cazares, Patric and Hyuri helped Mineiro to their third win in four games in Group 5.
After Cazares fired Mineiro into a second-minute lead, Patric then doubled the advantage in first-half stoppage-time after benefiting from a defensive mix up.
Hyuri - a second-half substitute - completed the scoring with a curled effort beyond Justo Villar in the 73rd minute.
The Strongest, meanwhile, stayed top of Group 1 following their last-gasp 1-1 draw against River Plate.
In a match that saw both teams reduced to 10 men in the closing stages, Alejandro Chumacero struck in the 90th minute to cancel out Rodrigo Mora's opener.
The Strongest top the group with seven points, two clear of River, and five ahead of Sao Paulo, who remain winless after three matches following a 1-1 stalemate at Trujillanos.