The hosts currently occupy second spot, while the opponents sit three points further back in third position.
Match preview
Cerro Porteno are within touching distance of a place in the last 16 of the Copa Libertadores after collecting eight points from their five group matches.
Wednesday's hosts began the competition in some style, picking up seven points from their opening three group matches.
However, a point from their last two Copa Libertadores contests has prevented Cerro Porteno from securing their place in the last 16 before the final matchday.
As long as they avoid defeat by a two-goal margin, Cerro Porteno will progress from the group, and they could still finish in top spot with two points separating them from Colon.
After thrashing Olimpia 4-0 in a league fixture at the weekend, the hosts will enter the midweek contest full of confidence as they look to replicate Sunday's result.
The visitors, meanwhile, have the chance to seek immediate revenge for the heavy defeat they suffered at the weekend.
Olimpia, who reside in third spot in Group G, picked up just two points from their opening group games before their hopes of reaching the last 16 received a boost when they edged out Penarol on matchday four.
However, a 2-1 defeat to Colon in their last group contest has left Olimpia three points adrift of Wednesday's opponents, while fourth-placed Penarol are only one point behind.
The visitors know that a victory by a two-goal margin will secure their passage to the last 16, although a draw or defeat could leave them open to losing third position, which would see them lose out on a Copa Sudamericana place.
Three consecutive away defeats in the Copa Libertadores will only dampen hopes of the visitors achieving a positive result on Wednesday.
Cerro Porteno Copa Libertadores form:
Cerro Porteno form (all competitions):
Olimpia Copa Libertadores form:
Olimpia form (all competitions):
Team News
The hosts are unable to call upon the services of Sergio Diaz and Alberto Espinola, who both miss out due to injury issues.
Robert Piris and Luis Farina returned from injuries to start in Sunday's superclasico, and the pair are expected to retain their places in the side.
There could also be a spot for Fernando Romero, who is set to return to the starting lineup after dropping down to the bench on Sunday.
As for the visitors, Antolin Alcaraz, Jorge Recalde and Walter Gonzalez could all miss out with injury problems.
Victor Salazar could return to the starting lineup if he manages to recover from an illness in time for Wednesday's contest.
After missing the last five games, Richard Ortiz could make his return from injury, but the 32-year-old may only be fit enough for a place on the bench.
Cerro Porteno possible starting lineup:
Jean; Rolon, Duarte, Patino, Rodriguez; Gimenez, Bobadilla, Piris, Noguera; Moreno, Farina
Olimpia possible starting lineup:
Olveira; Salazar, Gamarra, Salcedo, Otalvaro; Silva, Gomez, Candia, Cardozo; Paiva, Camacho