In the absence of Brazil from the process, these two sides were the favourites to qualify as top of the group. But the form of other sides, particularly Colombia, has left Uruguay in fourth, and Argentina are not running away with it, sitting only one point clear after seven games.
Uruguay's results in September were horrendous. Having been flattened 4-0 by Falcao's Colombia, they failed to beat Ecuador at home, meaning both of those sides are ahead of them in the qualification league. Now facing a trip to Argentina, they could end up slipping further down the table if they are beaten whilst Chile win.
Uruguay are the current champions of the continent, having won the Copa America in 2011 inspired by a series of incredible performances from Luis Suarez. It is he, along with Edinson Cavani, who will be relied upon the most to get a result in Argentina.
The task ahead of them is almost insurmountable. Argentina's current array of attacking talent means that Carlos Tevez, who would be the jewel in many international sides' crown, could not even make it into the squad.
Obviously there is Messi, fresh from his brace in the Clasico to deal with, but trying to focus on him may allow any of the plethora of other attackers to find space. Argentina have been very good at home, but Uruguay will have to hope they deliver a performance like the one that led to them drawing with Bolivia.
If Argentina do play anywhere near the level you'd expect it's hard to see Urugay stopping them, but their best hope will be to strangle as much space as possible and hope that Cavani or Suarez comes up with a bit of individual brilliance.
The exciting part of this game is the sheer number of players able to produce these kinds of moments that will be on the pitch. For the neutral staying up late, an early goal from Uruguay could make the game sensational, but the chances are Argentina will come out on top, and don't bet against some Messi magic.