Margarito (right) ended Cotto's reign in dramatic fashion
Previously unbeaten Miguel Cotto lost his WBA welterweight title when he was stopped by Mexican Antonio Margarito in the 11th round of their Las Vegas bout.
The Puerto Rican had won all 32 of his previous fights.
But he was sent to the canvas twice in the 11th, beating the count the first time before going down again, prompting his corner to throw in the towel.
Margarito, who gave up his IBF belt to fight Cotto, was leading 96-94 after 10 rounds on the cards of two judges.
A third judge scored it even, but Margarito finished the job in style to improve his own record to 37-5 with 27 wins inside the distance.
He now becomes a three-time welterweight champion, having vacated the IBF welterweight title in refusing to make a mandatory defence against the organisation's top contender, Joshua Clottey, in order to take on Cotto.
"I trusted my preparation coming into the fight," Margarito said. "Obviously Cotto is a great fighter but slowly the tornado rumbled and I told my corner I was going to knock him out - and I did."
Cotto was making the fifth defence of the title he won in 2 December 2006 by knocking out Carlos Quintana.
He out-boxed the taller Margarito through the early rounds, frequently landing a series of punches before dancing away from danger.
But Margarito, four inches taller than his opponent, continued to stalk Cotto and eventually began to wear down the smaller man by trapping him against the ropes.
In the seventh round a pair of Margarito upper-cuts found their mark and rattled Cotto, who began to bleed from his nose.
Margarito continued to chase his opponent down and inflicted further damage towards the end of the 10th round, sending Cotto back to his corner clearly exhausted.
The Mexican picked up where he left off at the start of the 11th, unleashing a flurry of punches with Cotto against the ropes before landing a number of further jarring blows on his opponent, who began to bleed profusely.
Margarito finally forced Cotto to his knee after a hard combination and then continued to unload as his opponent staggered around the ring, finally going down a second time as the towel flew in.
On the undercard, Colombian Cesar Canchila outpointed Giovanni Segura to claim the WBA interim light-flyweight championship.