Argentina have already qualified and it would take an unlikely combination of results for Uruguay to snatch another of the automatic berths but victory in Montevideo should go a long way to keeping them ranked in the world's top eight.
Uruguay seem destined for a play-off with Asia's Jordan and if they then make it to Brazil 2014, they would hope to be one of the eight seeds - based on world rankings - when the groups are drawn which should mean avoiding an early encounter with one of the favourites.
South America's oldest rivalry, dating back to 1901 when Argentina and Uruguay played their first friendly in Montevideo, resumes at the Centenario on Tuesday where the teams meet in their final qualifier.
"It's certainly an incentive to win the 'clasico' and if there's a chance we have to defend it (our ranking) to the death," said Uruguay captain Diego Lugano, whose team are number seven in the world.
Lugano, who led Uruguay to the 2010 World Cup semi-finals in South Africa, said that despite being one yellow card away from a suspension he would not hold back for fear of missing the first leg of next month's play-off.
"Those three points could seal our place as seeds and that's why they're very important," Uruguayan FA chief Sebastian Bauza said.
Coach Oscar Tabarez, on the other hand, gave little importance to the issue of seeding, saying: "It's not something that worries me.
"I recall that when the draw was made for 2010, we were practically receiving condolences because it was the group of death and I don't how many other things. It's all relative and the world won't end for us if we're not seeds."
Lugano and Tabarez have said the chances of qualifying directly on Tuesday defy logic since they need a big win and for Chile or Ecuador to win their match in Santiago by a large margin.
As things stand, with Uruguay three points behind both of them, Chile and Ecuador look set to take the last two automatic berths, sending the Uruguayans to the play-off. Colombia have already qualified alongside group winners Argentina.
Since then, Uruguay eliminated hosts Argentina in the 2011 Copa America quarter-finals on penalties and Lionel Messi's team exacted revenge with a 3-0 victory in their home qualifier in Mendoza a year ago.
Messi and several other first-choice players will be missing for Argentina, who booked their ticket to Brazil last month, with coach Alejandro Sabella poised to field even more reserves than on Friday when his side beat Peru 3-1 in Buenos Aires.