Brazilian side Bragantino eliminated Rosario Central in the last round, while Paraguayan opponents Libertad beat Santos on away goals to make it this far.
Match preview
Bragantino started the Brasileiro campaign in superb style and found themselves top of the pile eight games into the season, only to slowly slip down the division.
Mauricio Barbieri's side have gone three games without a win domestically and are now down in fifth place, 12 points behind leaders Atletico Mineiro.
The Red Bull-backed club are still on course for some continental success, though, after knocking out Independiente del Valle and Rosaria Central to reach the Sudamericana semis.
Competing in this tournament for a first time, Bragantino will enter their two-legged tie against Libertad with great confidence of advancing to November's final.
Either Penarol or fellow Brazilian side Athletic Paranaense await, but first Barbieri's men have to get the job done against Libertad.
The visitors are the reigning Paraguayan Primera Division champions, though they are down in sixth after the opening nine games of the current season.
Daniel Garnero's side beat River Plate 1-0 at the weekend to get their campaign back on track and now all focus is on this trip to Bragantino.
Libertad have already defeated one Brazilian side to make it this far, seeing off Santos on away goals following a 2-2 draw following victory over Junior in the last 16.
The Gumarelo have reached the semi-finals of the Copa Libertadores four times in the last 14 years, but never before have they advanced further on the continent.
Bragantino Copa Sudamericana form:
Bragantino form (all competitions):
Club Libertad Copa Sudamericana form:
Club Libertad form (all competitions):
Team News
Barbieri rested a number of key players for the draw with Bahia, with the likes of Weverton, Natan, Emiliano Martinez and Edimar being kept fresh for the visit of Libertad.
Each of those players could return in midweek as Bragantino go with their strongest possible lineup, while Gabriel Novaes is likely to get the nod up top over Ytalo.
As for Libertad, Garnero has used a 4-1-4-1 formation since the first leg of the quarter-finals against Santos and will almost certainly stick with that on Wednesday.
With his side getting back to winning ways last week, Garnero may keep changes to a minimum here, though Julio Enciso, Ivan Franco and Marcelo Fernandez are pushing for recalls.
Bragantino possible starting lineup:
Cleiton; Weverton, Bruno, Ortiz, Edilmar; Martinez, Ramires; Artur, Carvalho, Cuello; Novaes
Club Libertad possible starting lineup:
Silva; Mayada, Viera, Barboza, Vangioni; Bocanegra, Villalba H.Martinez, R.Martinez, Bogarin; Ferreira
We say: Bragantino 2-1 Club Libertad
Bragantino have won six and drawn one of their last seven games in this competition and proved too strong for Independiente del Valle and Rosario Central in the last two rounds.
Club Libertad have already eliminated one Brazilian side en route to the semis, but we can see them falling to a slender defeat in Wednesday's first leg.