Uruguay stalwarts Edinson Cavani and Luis Suarez are fighting for their World Cup survival, while Ghana will have revenge on their minds on Friday (at 10pm Cambodian time).
With Portugal having already qualified from Group H, Uruguay, Ghana and South Korea are battling for the other last 16 place in Qatar.
The key match will be a repeat of the infamous 2010 quarter-final in South Africa where Suarez broke Ghanaian hearts in one of the World Cup's most notorious moments.
Suarez prevented a certain goal with a deliberate handball on the goalline to deny Ghana an extra-time winner.
He was sent off but Asamoah Gyan missed the resulting spot kick, and Uruguay then won the penalty shootout to prevent Ghana becoming the first ever African nation to reach a World Cup semi-final.
Suarez on Thursday said he had no regrets.
"I don't say I apologise about that because I take the handball but the Ghana player missed the penalty, not me. It's not my fault because I did not miss the penalty," he said.
Ghanaian fans have not forgiven or forgotten.
"They gave us a very powerful defeat. We have never forgiven Suarez," said Ghanaian ruling-party lawmaker Collins Adomako-Mensah in Accra."Just as we cried 12 years ago, he will cry on Friday."
But Ghana coach Otto Addo has played down talk of revenge, saying his players would have acted in the same way – and he would want them to.
"This is what I wish from every player, to do all he can to help his team qualify, sacrificing himself with a red card," Addo said.
The permutations are simple for Uruguay – they must win to have any chance of progressing, while Ghana know a draw could be enough, depending on the result between Portugal and South Korea.
Like Uruguay, the Koreans must win and then hope for a favour in the other match.
They will be without Portuguese coach Paulo Bento after his red card in the 3-2 defeat to Ghana when he raged at the referee.