Wise Dan beat Animal Kingdom with Excelebration out of the places in the Breeders' Cup Mile at Santa Anita on Saturday.
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Charles Lopresti's horse took over from the front-running Obviously in the straight and powered home in a course record 1min31.78secs.
Obviously held on in a photo for third with Excelebration fourth and Animal Kingdom, the 2011 Kentucky Derby winner, finishing well to take second.
Aidan O'Brien was understandably deflated by the performance of Excelebration, who was so impressive in the Queen Elizabeth II Stakes at Ascot last month and is now set to be retired to stud.
He said: "We felt we had to give it a go, but the edge just wasn't on him today.
"He was very impressive at Ascot, but that was only 13 days ago and it may well have left its mark.
"Joseph (O'Brien, jockey) said that going left-handed first time was also a contributing factor."
Even more disappointing was Moonlight Cloud, who beat just one horse home.
Her jockey, Thierry Jarnet, said: "It was difficult out there - there were a lot of horses moving about early on.
"She had no speed at the finish."
Winning jockey John Velazquez said of Wise Dan's length-and-a-half victory: "He's a special horse.
"He's a pleasure to ride. He lets you do what you want.
"He's got better with age."
Animal Kingdom's trainer Graham Motion said: "We hoped he'd would run like this - it's thrilling.
"He's a very special horse - an amazing horse - and he's proved that today."