Van Nistelrooy has singled out Red Devils' hitman Van Persie and Madrid's former United forward Ronaldo as the deciding factors.
"For me the difference will be the form of Cristiano and Van Persie. I think that one of these two players will make the difference," Van Nistelrooy told Marca.
"Both teams are doing very well. I think Madrid have improved a lot in recent weeks. Taking away the Granada game (1-0 loss) I see a strong team, who played very well against Barca and who show their best in the big games.
"I think the tie will be decided by the smallest details."