Figures compiled by industry body Pollstar show the venue sold 2,349,252 tickets in 2009 - 75% more than any other venue worldwide - smashing its previous record of 1,806,447 tickets by 30%.
Since opening in 2007 the former Millennium Dome, now operated by AEG Europe, has hosted some of the world's best music, sport and entertainment events.
Highlights for 2009 include an eight-night residency from Britney Spears; Star Wars: A Musical Journey; and the inaugural Barclays ATP World Tour Finals.
This year the venue has more exclusive events planned, including the world's biggest screening of Mamma Mia! The Movie; Julie Andrews's return to the London stage; and the venue's first full-blown opera, Carmen.
"Congratulations to AEG for the astonishing success of The O2," said Mayor of London Boris Johnson. "The superb facilities it offers have increased London's ability to attract the biggest music stars in the world, and an increasing number of international sporting events."
David Campbell, president and chief executive of AEG Europe, said: "These results really are quite amazing. Events such as the ATP Tour Finals at The O2 really did put the eyes of the world on us. London deserves a world-class entertainment destination and we will keep working hard in the next decade to ensure we remain a world leader."
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