The sides find themselves level on points after five outings, with the visitors leading on goal difference, meaning the home team must take all three points to qualify in the top two.
Match preview
After finishing second in the top flight last season and winning the Supercopa de Chile, Colo-Colo headed into the new Copa Libertadores campaign with high hopes, and they made a positive start to the group stage.
Los Albos began with a trip to Fortaleza, and they beat Wednesday's opponents 2-1 thanks to goals from Juan Martin Lucero and Pablo Solari, before making it back-to-back victories as they defeated Alianza Lima by the same scoreline on home turf.
Lucero was again on the scoresheet alongside Esteban Pavez in that triumph, but Colo-Colo have since been unable to add another notch to their wins column, as they were then beaten 2-1 by River Plate before settling for a 1-1 draw away at Alianza Lima.
Gustavo Quinteros's side most recently travelled to Argentina for their reverse fixture against River Plate, and they were on the wrong end of a 4-0 thrashing, leaving them third in the group behind Wednesday's opponents on goal difference.
Currently leading the Chilean Primera Division narrowly, Colo-Colo will be desperate to add to their campaign by booking their spot in the Copa Libertadores knockout stage, rather than dropping into the Copa Sudamericana in third spot, although they come into the game knowing they require a victory.
Fortaleza, meanwhile, will make the trip looking to keep hold of second spot, having had a contrasting group campaign thus far.
Wednesday's visitors bypassed the Copa Libertadores qualifiers as they snuck into the top four of the Campeonato Brasileiro Serie A on the final day of last season, but they have had to endure a poor start this time around, currently sitting at the foot of the division and without a win from their opening six outings.
Their continental campaign got off to a similarly tough start, as they lost the opening two games to Colo-Colo and River Plate, before putting their first points on the board with a 2-1 victory over Alianza Lima.
After being the first team to hold River Plate to a draw in the group, Juan Pablo Vojvoda's side put a second three-point haul on the board in their most recent Copa Libertadores game, as Moises and Yago Pikachu netted goals in a 2-0 win away at Alianza Lima.
Having now put themselves in pole position to reach the knockout stage, the Leao do Pici will aim to cement their second-placed finish with a positive result in Chile on Wednesday.
Colo-Colo Copa Libertadores form:
Colo-Colo form (all competitions):
Fortaleza Copa Libertadores form:
Fortaleza form (all competitions):
Team News
Colo-Colo's attack will be led by star man Juan Martin Lucero, who has netted four goals in five group-stage games this season.
Gabriel Costa will be available to play, despite getting sent off in their recent league meeting with O'Higgins, as his suspension will instead carry over to their next domestic match.
Experienced midfielder Esteban Pavez has been an ever-present in their Copa Libertadores campaign, and he will continue to operate in the engine room, while centre-back Maximiliano Falcon has also played in every minute of the group stage thus far.
Fortaleza may come into the game with an unchanged starting XI from their win away at Alianza Lima, with Moises set to feature in attack, having netted his first Copa Libertadores goal of the season in that game.
Renato Kayzer and Silvio Romero will likely battle for the second place up front, while Yago Pikachu is another attacking threat, with the 29-year-old boasting nine goals in all competitions so far this season, having also provided four assists in five group-stage games.
Colo-Colo possible starting lineup:
Cortes; Opazo, Falcon, Amor, Suazo; Fuentes, Pavez; Solari, Gil, Costa; Lucero
Fortaleza possible starting lineup:
Boeck; Tinga, Titi, Benevenuto; Pikachu, Felipe, Jussa, Crispim; Lima; Kayzer, Moises
We say: Colo-Colo 2-1 Fortaleza
Fortaleza have done well to put themselves ahead in the fight for second spot, but they face a particularly tough test on Wednesday and we see them falling short on their travels.