Cerro – winners of Paraguay's Clausura last term – will be buoyant after a 4-0 league drubbing of Sportivo Luqueno on Saturday.
Leonardo Astrada's side were utterly dominant as they moved up to fourth in the Clausura league table, with Jose Maria Ortigoza netting a double.
Bruno Valdez and substitute Rodolfo Gamarra also scored in Cerro's morale-boosting triumph.
And they will need that confidence as they look to overturn Independiente's 1-0 first-leg lead on Tuesday.
The Ecuador side beat Cerro last week thanks to Arturo Mina's 56th-minute goal and know avoiding defeat will be enough to book their place in the competition's last 16.
It is one of seven round-of-32 clashes to be played this week, with Deportivo Capiata and General Diaz – also from Paraguay – both in action.
Both Deportivo and General have made slow starts to their Clausura campaigns but can boost spirits with continental progression.
Deportivo drew their first leg 1-1 at home to Caracas and could be made to rue Romulo Utero's stoppage-time equaliser for the Venezuelan outfit.
General's progression looks more likely, though, after they won the opener 2-0 at Colombia's Atletico Nacional.
Uruguay giants Penarol could face a tough challenge against Deportivo Cali of Colombia.
Cali came from behind twice in the first leg to earn a 2-2 draw on their travels.
Elsewhere, Club Universitario and Cesar Vallejo's tie is evenly poised after a 2-2 first-leg draw, while River Plate of Uruguay will aim to reverse a 2-1 deficit against Emelec.
And Chile's Huachipato travel to Ecuador to meet Universidad Catolica with a 2-0 advantage.
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