The film comes 20 years after the Simpsons made their TV debut
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The Simpsons' transition to the big screen has proved a success, with their first movie topping the North American box office in its opening weekend.
The film, which sees the animated family chased out of Springfield for causing an environmental disaster, took $72m (£36m) between Friday and Sunday.
It knocked last week's number one, the Adam Sandler comedy I Now Pronounce You Chuck and Larry, into second place.
Harry Potter and the Order of the Phoenix fell to number three.
Hairspray, starring John Travolta in a big-screen version of the Broadway musical, was also down one place at number four.
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NORTH AMERICAN BOX OFFICE
1. The Simpsons' Movie ($71.9m)
2. I Now Pronounce You Chuck and Larry ($19.1m)
3. Harry Potter and the Order of the Phoenix ($12.5m)
4. Hairspray (above, $15.6m)
5. No Reservations ($11.8m)
6. Transformers ($11.5m)
7. Ratatouille ($7.2m)
8. Live Free or Die Hard ($5.4m)
9. I Know Who Killed Me ($3.4m)
10. Who's Your Caddy? ($2.9m)
Source: Media By Numbers
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The tale of an unpopular teenager who is desperate to appear on a TV talent show, the film also features Michelle Pfeiffer and Queen Latifah.
Catherine Zeta-Jones stars in the week's second-highest new entry, romantic comedy No Reservations at five.
But troubled actress Lindsay Lohan suffered another setback as her latest film, I Know Who Killed Me, struggled to break into the top 10 - landing at number nine, taking just $3.4m (£1.7m).
Lohan was arrested in Los Angeles last week for suspected drink driving and cocaine possession after a high-speed car chase.
The Simpsons Movie cost a reported $75m (£37m) to make. Once foreign box office receipts are added to the US tally, the hand-drawn animation is expected to have turned a profit in its first week.
"Homer's odyssey paid off," said Paul Dergarabedian, president of box office analysts Media By Numbers.
"We are ecstatic," said Chris Aronson, senior vice-president for distribution at film studio 20th Century Fox. "It far exceeded even the most optimistic of expectations."
The Simpsons made their TV debut in 1987 on Tracey Ullman's US TV sketch show.