Preliminary reports say Manuel Uribe died due to an irregular heartbeat and an ailment linked to the loss of fluids in his legs, an official at the University Hospital in the northern city of Monterrey told AFP.
After he was listed as the world's heaviest human by the Guinness World Records in 2007, Uribe began a diet that brought his weight down to 394 kilos.
But he was taken to the hospital on May 2, transported with a crane from his home in the town of San Nicolas de los Garza because he could not walk.
Uribe got married in 2008 after being taken to the ceremony in a crane. A US television station had bought the broadcast rights for the event.
Mexico is battling an obesity epidemic, with 71 percent of adults and a third of children considered overweight or obese, figures that rival the United States for the dubious title of the world's heaviest nation.