Both clubs played out 1-1 draws in the opening group game last week, as Santa Fe travelled to Atletico Junior, while Fluminense took on River Plate in Rio de Janeiro.
Santa Fe took on Colombian rivals Junior in their first game of the group stage, and they got off to a poor start as Fredy Hinestroza put the hosts ahead on the 30-minute mark.
Harold Rivera's side replied instantly though, as they won a penalty in the 35th minute which Kelvin Osorio converted to equalise, with the match finishing level despite Santa Fe's Carlos Arboleda being shown a red card with 20 minutes to go.
They then played Junior away for the second consecutive time last time out, as the sides battled in the first leg of their Categoria Primera A quarter-final clash.
The hosts took a 3-0 lead through a Luis Gonzalez goal and a Miguel Borja brace, but Jeison Palacios found the net for Santa Fe on the hour mark to give his side a small chance going into the second leg.
Rivera's men will now turn their attention back to the Copa Libertadores, as they look to record a crucial victory to move into the top two of the group.
Their opponents come into this game in exactly the same situation, as all four sides in group D jostle to move off one point and assert their dominance.
Fluminense picked up a point from their first group game, as they hosted Argentinian giants River Plate.
They then returned to winning ways last time out, as they defeated Madureira 4-1 in the final league game of the Carioca Serie A, sealing their second-placed finish and a favourable semi-final tie as a result.
Despite accumulating 31 state championships and four top-flight titles in Brazil, the Tricolor Machine are yet to lift South America's elite trophy, with their most notable recent campaign coming in 2008, when they reached the final and lost to LDU Quito in a penalty shootout after a 5-5 aggregate draw over two legs in the final.
For now, their focus will be on qualifying for the final 16, with a win on Thursday majorly boosting their chances of progressing out of the group.
Santa Fe will be without right-back Carlos Arboleda for this game, as he will serve a suspension for the red card shown in their opening Copa Libertadores clash with Junior.
In his absence, Alexander Porras could come into the back four, after he made a substitute appearance in that game.
Veteran striker Fred will lead the line for Fluminense, having netted the equaliser in the draw with River Plate.
He will be supported by 17-year-old winger Kayky, who will feature until the end of the season for Fluminense after confirming a move to Manchester City recently.
Santa Fe possible starting lineup:
Castellanos; Porras, Torijano, Palacios, Mosquera; Pico, Giraldo; Caballero, Arias, Osorio; Ramos
Fluminense possible starting lineup:
Marcos; Calegari, Nino, Claro, Egidio; Yago, Martinelli; Henrique, Nene, Kayky; Fred
We say: Santa Fe 1-1 Fluminense
We would not be surprised to see both sides move onto two draws from two games in the group, as we cannot separate them going into Thursday's clash.
Both teams have the ability to cause the other side problems, and we see them cancelling each other out as neither risk suffering a defeat.
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