The raucous film, a big-screen spin-off of the popular British sitcom, took $21 million (£13 million) in sales, seeing off Hollywood blockbusters Rise of the Planet of the Apes and Cowboys & Aliens to take the top spot.
The comedy, which focuses on a group of teenage boys enjoying a summer holiday in Greece, stole the record previously held by Bridget Jones: The Edge of Reason, which took $16 million (£10 million) on the weekend of its release in 2004.
The Inbetweeners Movie's producer, Chris Young, says, "We are thrilled that The Inbetweeners Movie is the biggest opening of all time for a U.K. comedy. We really want to thank all the cinemagoers out there who have made the film such a huge success."
Full details of the weekend's takings at the U.K. box office will be revealed on Tuesday (23Aug11).