Vertonghen believes that Spurs have a massive benefit with the game being played at Wembley.
Spurs have been using Wembley as their home stadium this season - given the rebuilding going on at White Hart Lane.
Tottenham beat United at the same ground in the league a couple of months ago.
"Wembley is definitely not a disadvantage," Vertonghen said to the Daily Star.
"We're used to it now, even if the atmosphere will be a bit different because United will bring more supporters than usual.
"We feel very comfortable at Wembley, we've shown that over the last couple of months – not against Manchester City but before that we felt very comfortable.
"Hopefully we can have the same game as at the beginning of this year when we beat United in a very positive way."