The fire gutted the lakeside Kandawgyi Palace Hotel, a colonial-era building owned by a Myanmar businessman notorious for making his fortune under the former junta.
Hundreds of firefighters tried to quell the blaze which broke out at around 3am local time (2030 GMT), but they could not stop the flames from consuming the luxury hotel.
An AFP reporter at the scene saw a white plastic sheet covering a body retrieved from the fire, but there was no immediate confirmation of further casualties.
Another witness, wearing a branded shirt of the Htoo company which owns the hotel, said: "It is really bad. All has gone now."
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The Htoo company, which spans construction, timber, resorts and an airline, was founded by Tay Za - a controversial tycoon who spun millions of dollars through close junta links.
Guests at the destroyed hotel had been moved to other hotels in Yangon, Myanmar's largest city which has made its mark on Southeast Asia's tourist trail since the country emerged from full junta rule.
Myanmar's reputation as one of the region's hottest new destinations has also been battered by global censure over an army crackdown on its Rohingya population.