The fifth installment of the franchise is the second-highest opening for the series since Mission Impossible II‘s $57.8 million in 2000.
According to box office analysts Rentrak, 62% of the opening weekend audiences were male, and 81% over 25.
Tom Cruise pulled off a turnaround after a string of underperforming movies, including Jack Reacher and Edge of Tomorrow, and managed to sidestep awkward questions about his belief in Scientology.
Vacation, billed as a semi-sequel to the classic 1983 National Lampoon road trip comedy, starring Chevy Chase, opened second with takings of $14.9 million.
Reviews of the comedy have not been particularly kind and, according to exit polls, audiences gave the film a B CinemaScore.
The already released Ant-Man, Minions and Pixels rounded out the top five.
North American box office Top 5:
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