When: Saturday, June 19, 01:00 BST (Sunday)
How to watch: BBC red button
In a group also consisting of Chile, Paraguay and Bolivia, it is firmly expected that these two nations will be the ones filling the top spots come the end of the group stage.
This meeting in the early hours on Saturday holds importance concerning the quarter final draw, with first place facing fourth in Group B and second playing third in the other group.
The match on paper seems as though it will be a low scoring affair, as Uruguay have failed to hit the net in their previous three matches against Venezuela, Paraguay and Brazil respectively.
That means they will likely need Luis Suarez and Edinson Cavani to rediscover their goal scoring touch if they are to defeat the Argentinians.
Argentina themselves lacked any real cutting edge against Chile in their opener and were toothless in front of goal.
Their one moment of magic was provided by none other than Lionel Messi, who scored a wonderful free kick to put his team 1-0 up.
The group favourites were pegged back when Arturo Vidal had his penalty tipped onto the crossbar by Aston Villa goalkeeper Emiliano Martinez, but striker Eduardo Vargas was there to notch from the follow up with his head.
It looks like being a battle between two teams who are closely matched and one moment of magic could be the difference in Brasilia.
Last three meetings:
Argentina 2-2 Uruguay (Friendly - November 18, 2019)
The two South American rivals played out a draw the last time the sides met. Lionel Messi was, as he so often is, the man of the moment as his late penalty extended Argentina's unbeaten run against Uruguay to four matches.
Three of football's other top goalscorers also got their names on the scoresheet. Edinson Cavani scored in the first half, with Sergio Aguero cancelling out the opener in the 63rd minute.
Uruguay 0-0 Argentina (World Cup qualifier - August 31, 2017)
Jorge Sampaoli took charge of his first competitive game in charge of Argentina but he was not able to see his struggling side change their fortunes.
Few chances were created and none were taken as Lionel Messi grew into the game, but was not able to have an important say regarding the scoreline.
The draw left Argentina in a disappointing fifth place in the Copa Sudamerica table, whilst Uruguay did their World Cup qualification hopes no harm and found themselves in third place following the stalemate.
Argentina 1-0 Uruguay (World Cup qualifier - September 2, 2016)
Lionel Messi returned to international football to help his country to an important victory over rivals Uruguay.
Messi retired from international football only a couple of months before, but the Barcelona superstar made his comeback here and delivered the goods for Argentina.
In a game scattered with cards, Paulo Dybala was sent off for the hosts for a second yellow card on the stroke of half time, but Messi had netted his 56th goal for his nation just a few minutes prior and his team held on for the entirety of the second half for victory.
Argentina wins: 87
Uruguay wins: 57
What can we expect?
Judging from recent meetings of these two South American giants: not many goals and lots of cards. A tight affair seems on the cards and the last two meetings have ended in stalemate.
There were four cards shown in the previous meetings and that was only a friendly so this competitive fixture could provide even more cards.
In fact, the last four games have seen an incredible 24 cards shown and this match seems sure to provide more of the same and follow the trend.
From a goals angle, Uruguay have certainly been struggling to hit the net and, although Argentina's defence can be shaky, Cavani and Suarez need to show up if Uruguay want to hit the net.
Lautaro Martinez seems to be Argentina's first-choice striker at present following a strong season for Serie A winners Inter Milan.
However, the 23-year-old has faced criticism for his lack of goal scoring from Argentina fans and once again lacked any spark against Chile in his side's opener.
Like Cavani and Suarez, he is a proven goalscorer but certainly needs to rediscover his form.
Lionel Messi is the key man without any doubt and the left-footed superstar can make something happen from nothing, as he did in Argentina's first group game.
The Barcelona man can add to his tally of four goals against Uruguay, who can be exposed defensively and Messi will look to take advantage.
He is generously priced at 5/2 to open the scoring and evens to score at any time in the 90 minutes.
Uruguay desperately need their spark back in front of goal and Edinson Cavani could provide that. Cavani has plenty of experience and boasts 51 goals on the international stage.
The lethal finisher is 11/2 to score first and 11/5 to score any time against Argentina.