Alvaro Gutierrez's men currently occupy third place in the section with seven points to their name, while their visitors are sitting pretty at the top and can confirm a spot in the knockout rounds with another maximum.
Match preview
With Venezuelan whipping boys Metropolitanos cut adrift at the foot of Group B with zero points to their name, it is shaping up to be a tantalising three-horse race between Nacional, Internacional and second-placed Independiente Medellin for Copa Libertadores knockout berths.
Having posted two wins, one draw and one defeat from their four games so far, Nacional's tally of seven points is currently only good enough for third place, which would demote them to the Copa Sudamericana, but Gutierrez's side are just one point adrift of Internacional and only behind Medellin on goal difference.
The Uruguayan champions were leapfrogged by Medellin on matchday four, failing to hang onto a 1-0 lead as the Colombians struck back through Andres Ibarguen and Deinner Quinones, and few will expect Medellin to slip up against Metropolitanos in the penultimate round of fixtures this week.
Holding their own against Internacional is therefore imperative for Nacional, but the hosts have won just one of their last five games heading into Wednesday's affair and needed a 78th-minute Gaston Pereiro effort to hold Cerro to a 1-1 draw at the weekend in the Uruguayan Primera Division.
Nacional find themselves four points adrift of leaders Penarol in the top-flight table with just over half of the season played, but they are currently on a nine-game scoring streak in all competitions and have prevailed in each of their last six home contests, netting at least twice each time.
While Nacional cannot seal a top-two finish no matter what transpires this week, their Brazilian adversaries Internacional need only travel back to base with all three points in the bag to assure themselves of a place in the knockout stages for the fourth time in five seasons.
Still unbeaten in the section with two wins and two draws to their name, Mano Menezes's charges put Metropolitanos to the sword 2-1 on matchday four thanks to Luiz Adriano and Alan Patrick's goals, and both sides ended the game with 10 men following a bad-tempered final 10 minutes.
Internacional could even guarantee a first-placed finish with a win if Metropolitanos can stun Medellin, but their league fortunes have suffered greatly, as Menezes's side are languishing in 13th place in the Brasileiro table with just 11 points taken from their first nine games of the 2023 season.
The visitors have hardly made a bright start to June either, as they were knocked out of the Copa do Brasil on penalties by America Mineiro and were held to a 1-1 draw with Santos at the weekend, meaning that they travel to Uruguay having only prevailed in one of their last six away matches.
However, recent history favours the Brazilians, who have gone unbeaten in their last four meetings with Nacional since a 3-1 group-stage defeat in 2007, but Gutierrez's side came from behind twice to hold Internacional to a 2-2 draw in early May.
Nacional Copa Libertadores form:
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W
D
L
Nacional form (all competitions):
W
D
D
W
L
D
Internacional Copa Libertadores form:
D
W
D
W
Internacional form (all competitions):
L
L
W
W
L
D
Team News
Nacional midfielder Diego Rodriguez looked a bit worse for wear as he came off at half time in the recent draw with Cerro, but Gutierrez affirmed after the game that his withdrawal was a tactical one, and he should be fine to line up on Wednesday.
However, the same cannot be said for 19-year-old attacker Renzo Sanchez, who is nursing a cruciate ligament injury, while Pereiro and left-back Camilo Candido must both serve one-game suspensions for a totting-up of yellow cards.
Pereiro would have most likely been restricted to a place on the bench anyway, but Candido's absence is more troubling for Gutierrez, who should call upon 33-year-old Christian Almeida to fill the void at the back.
Similarly, Internacional must also find a solution to Nicolas Hernandez's suspension following the centre-back's late red card against Metropolitanos, and Menezes could have therefore done without his other centre-back Vitao exiting with a knee injury against Santos.
However, his affliction is not expected to prevent him from playing on Wednesday, leaving former Barcelona protege Igor Gomes to battle Felipe Motta for a start in place of Hernandez, and the former should win that head-to-head.
Campanharo, Rodrigo Moledo, Pedro Henrique, Gabriel Mercado, Mauricio and Gabriel also take up spots in the visitors' well-occupied infirmary, while ex-Bayer Leverkusen lynchpin Charles Aranguiz is struggling with a calf concern and should miss out too.
Nacional possible starting lineup:
Rochet; Lozano, Noguera, Polenta, Almeida; Y. Rodriguez, D. Rodriguez; Trezza, Zabala, Fagundez; Ramirez
Internacional possible starting lineup:
Keiller; Bustos, Vitao, Gomes, Lara; Romulo, Johnny; De Pena, Patrick, Wanderson; Adriano
We say: Nacional 2-1 Internacional
Despite their satisfactory record against Nacional, Internacional's plethora of absentees will have their Uruguayan hosts licking their lips at the prospect of revenge, especially with Gutierrez's side on top form in front of their own fans.