The 2010 World Cup winners are top of Group G on goal difference, having conceded one goal fewer and scored three more than second-placed Italy.
A late Daniele De Rossi equaliser denied Spain victory in the corresponding fixture in October 2016, when Vitolo netted first in a 1-1 draw, but a win over the Azzurri at Santiago Bernabeu would make Julen Lopetegui's side firm favourites to top the group and leave Italy hoping to qualify via the play-offs.
"Spain are the favourites, but not by much," Ronaldo told La Gazzetta dello Sport.
"The only advantage is they are playing in Madrid and I read Italy haven't beaten them on their own turf in almost 70 years, so that must mean something.
"The Spanish defence is in its full maturity too and Sergio Ramos is probably the best defender in the world right now.
"On paper, Spain can cause the most problems for Italy in midfield, especially with Isco and Marcos Asensio, who are so tough to face right now. They have so much quality, freshness and self-confidence that you can't study ways to limit them."
Ronaldo earned legendary status in La Liga and Serie A during his days as a player with Barcelona, Inter, Real Madrid and AC Milan, and he feels it would be a shame for either Spain or Italy to fail to reach the World Cup in Russia.
"I'm almost sorry this game is being played," he said.
"The draw was cruel, as it's not right that weaker teams in other groups are guaranteed qualification and one of these two must go through a play-off, risking a World Cup exit.
"There is great reciprocal respect between these sides. Italy are Italy, they are never easy to face and that has always been the situation."