Van Nistelrooy, who spent five years at United before moving to Madrid in 2006 for a four-year spell at the Bernabeu, finds it impossible to pick a favourite between the two European superpowers and believes the last-16 tie will be settled by the "smallest details".
To that end he 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."
The 36-year-old Dutchman feels Madrid, who are looking for a record 10th European Cup crown, boast more quality than Sir Alex Ferguson's side but has warned the Spanish giants that United's "lethal" strikeforce of Van Persie and Wayne Rooney will take some stopping.
"I think they (Madrid) have more quality on the pitch. But United win and win every week. They trail 2-0 and fight back, they go 1-0 up and control the game.
"United are very much a team. They defend all together and then play for Van Persie and Rooney.
"Madrid, due to injuries, have not been able to create such a solid group and be able to repeat the same team every week.
"Pepe and Marcelo have been injured, (Gonzalo) Higuain and (Karim) Benzema haven't been doing well, (Angel) Di Maria doesn't always play...The injury to Iker (Casillas) doesn't help either because he's always there and very experienced.
"It will be a very interesting game."
Asked what Madrid need to fear, Van Nistelrooy said: "United don't need many chances to score. Give one to Van Persie and Rooney and it's going in. They don't miss. And the problem is that they always create something.
"They are a lethal pair."
The first leg takes place at the Bernabeu on Wednesday.