The 62-year-old coach has experience in Champions League ties at Manchester United's stadium having being involved in two thrillers with the Red Devils in 2000 & 2003
With Madrid all but out of contention for la Liga, coach Jose Mourinho is under pressure to grab that elusive 10th Champions League success, but first he must overcome the Red Devils in the last 16 in what could be a season defining moment.
The scenario bears an uncanny resemblance to the situation Del Bosque faced back in 2000 when his Madrid side, who were out of the Liga race, took on the Premier League giants in the quarter-finals and won the second leg at Old Trafford 3-2 to progress to the semi-finals.
"The first time, in the '99-'00 season. It was a game I'll never forget. It was our first year. We had drawn nil-nil at home, and our season depended on it," he told Marca.
"We changed our system to play with three centre-backs. It was a good thing we won. They would have killed us otherwise. We were doing badly in the league and we were outside of the European spots.
"I was really scared of United's strikers: Cole and Yorke. They really opened up the pitch with Beckham and Giggs and I tried to reinforce the central defence with those three centre-backs: Ivan Campo, [Ivan] Helguera and [Aitor] Karanka."
The Furia Roja coach also fondly recalled the impact Ronaldo had at Old Trafford in Madrid's 4-3 defeat in 2003.
"Everyone remembers the three goals by Ronaldo," he added. "What an ability he has to score! The Brazilian was a very positive player, one of those people who are happy just playing football."