Defending Copa Libertadores champions Atletico Mineiro must overturn a one-goal deficit if they are to reach the quarter-finals.
The Brazilian giants suffered a 1-0 loss at Atletico Nacional in the first leg of their round-of-16 tie, and they will welcome a return to their Estadio Governador Magalhaes Pinto home.
A three-match winless run in all competitions led to the sacking of coach Paulo Autuori, who was dismissed just hours after the loss in Colombia.
Levir Culpi signed a contract until the end of the year for his fourth stint at the club, but his latest spell started with a 2-1 loss at Gremio in Brazil's Serie A.
It marks a tricky period for Mineiro, who have the likes of Ronaldinho, Jo and Nicolas Otamendi starting regularly.
With the away-goals rule in place, the visiting Atletico Nacional know just one goal will make it tough for Mineiro.
Sherman Cardenas struck a stunning late winner in the first leg, and the Colombia Primera A's top side have enjoyed a good campaign.
Most ties are generally even heading into the second leg, although Bolivia's The Strongest go into their trip to Uruguay to face Defensor Sporting with a 2-0 lead.
That two-goal advantage is the biggest of the remaining ties.
Brazil's Gremio must come from behind if they are to progress, hosting San Lorenzo after the Argentine outfit claimed a 1-0 first-leg win.
Argentina's Velez Sarsfield welcome Paraguayans Nacional Asuncion to the Estadio Jose Amalfitani, with the Paraguayans having won the first leg 1-0.
Cerro Porteno, of Paraguay, are well-placed to advance as they host Cruzeiro having played out a 1-1 draw in Brazil.
Chilean outfit Union Espanola host Arsenal after the first leg between the sides finished goalless.