Spanish media outlet Don Balon say the Portuguese superstar reckons the former Malaga midfielder is the rotten apple in the group.
It’s suggested Ronaldo – and Karim Benzema – prefer the balance of the team when Isco is omitted.
They both reportedly favour Marcos Asensio in the 1st XI.
Ronaldo’s apparent grudge against Isco won’t be popular with the Real faithful.
The Spaniard was a standout performer last term and earned rave reviews for a series of standout displays.
Real are having difficult season and could only manage a 0-0 draw with Atletico Madrid in La Liga on Saturday.
The result leaves them a hefty 10 points of pace setters Barcelona in the title race.
Real did bounce back in the Champions League last night, though.
They cruised to a 6-0 win over Cypriot outfit Apoel – without Isco in the team.
Ronaldo and Benzema both scored twice in the rout.
Luka Modric and Nacho also got in on the act.
The win eased some pressure on Zinedine Zidane.
Speaking after the game, he said: “We are on the right track and doing things well.
“We continue to grow in the game because it is never easy to get six goals away from home.
“We can say that it has been a game against a weak opponent, but it is not true. We played a serious game, we scored early and kept a clean sheet.”