The 33-year-old will lock horns with six of his Real Madrid team-mates as the Spaniards attempt to shrug off the shock sacking of coach Julen Lopetegui following the announcement that he will take over at the Bernabeu next month.
It is worth wondering what Ronaldo might have known of Lopetegui's imminent appointment at Real, given the relationship both have with Portuguese super-agent Jorge Mendes, at a time when the forward's own club future remains the source of speculation.
But now, amid all that, Ronaldo's focus is on the World Cup, the one major honour still missing from his CV.
It is a stretch to make Portugal one of the favourites to win the trophy, even with Ronaldo, but they are nevertheless in Russia as the reigning European champions after surprising France on home soil two years ago.
Ronaldo is 33 now, still in fantastic physical condition and the reigning Ballon d'Or winner. He can probably play on for as long as he wants, but it is hard to imagine him returning for a fifth World Cup in Qatar in 2022.
If he is to cap his career with a World Cup winner's medal, then now is his time, and what better way to start than by inspiring Portugal to victory over their neighbours and put themselves in pole position in Group B.
"Of course Cristiano Ronaldo is the best player in the world at the moment and he will be the top player at this World Cup. There are no words to describe him," said admiring team-mate Joao Mario at Portugal's base near Moscow this week.
Ronaldo was playing the last time Portugal beat their rivals in a major tournament, winning 1-0 to eliminate Spain in the group stage at Euro 2004.
He was just 19 then, and has gone on to become his country's leading scorer with 81 international goals.
He won his 150th cap in the recent friendly against Algeria. And yet he has never quite managed to replicate his club form on the major tournament stage.
He lasted just 25 minutes before coming off injured in the Euro 2016 final, watching from the sidelines as Eder's extra-time goal shocked France.
At the World Cup so far, Ronaldo has managed just three goals in three tournaments: a penalty against Iran in 2006; one against North Korea in 2010, and one against Ghana in 2014.
There will be an obvious determination to improve that record in Russia, with Portugal also facing Morocco and Iran in their group.
But he also needs to act as a father figure to the talented young members of Fernando Santos's squad, like Bernardo Silva, Goncalo Guedes and Gelson Martins.
The latter is one of four Portugal players -- along with William Carvalho, Bruno Fernandes and Rui Patricio -- who say they will be breaking their contracts with Ronaldo's first club, Sporting Lisbon, after being attacked by disgruntled fans last month.
Ronaldo has a responsibility to unite the squad and focus minds ahead of his fourth World Cup.
"Ronaldo is our captain, he sets an example for us and is advising us younger players and sharing his experience," said Manchester City's Silva.
That experience, and inside knowledge of many of the Spain players, will be crucial on Friday by the Black Sea.