One player who could significantly help Uruguay in trying to contain Ronaldo is defender Jose Maria Gimenez, who missed the group stage finale with a thigh injury.
There has been little love lost when they have met: Ronaldo once punched Godin during a Spanish Super Cup tie, but the defender got his own back in a meeting a year ago by elbowing the Portuguese in the head.
Uruguay won all three of their group matches, beating hosts Russian Federation 3-0 in their last outing, and are the only team yet to concede a goal at the tournament.
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Raphael Guerreiro and Gelson Martins are in contention to play in the next match after returning to full training while William Carvalho is a doubt after missing one training session. "Not just Godin. We will have to work collectively in order to try and limit the effect that he can have".
The two teams juxtapose one another nicely heading into what could be a frantic round-of-16 clash, too.
Whether he can break through against Uruguay will determine Ronaldo's World Cup legacy.
"The important thing is to think about the [round of 16] match, think about the game, get to know your adversaries and then to get well prepared mentally and physically, regardless of it being Uruguay or the hosts", Santos said of his team's progress.
And Uruguay has identified Ronaldo, with four goals so far at Russian Federation 2018, as the biggest threat to their hopes of a place in the last eight.
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"Considering the limitations we have as a country in footballing terms, we have come into this World Cup just as we wanted and in the three games we have played so far I think we are closer than ever to what we want to be".
"We'll be focused. But nine of those Portuguese players on that pitch are European Champions".
"We have made it to the World Cup and, in the last three matches, we have shown what we want to achieve".
"I have to repeat it time and time again, " Santos said. I've told them they need to be calm. This a World Cup. Whatever happens to other teams is interesting for other people - people who analyse the results - but we're not interested.
Brazil cruise into last 16 by beating Serbia
Brazil struggled in their opening two matches, first held to a 1-1 draw and then needing late goals to win the other. Serbia needed to win to qualify and rocked their opponents with a flurry of second-half chances.