Sergei Bagapsh, president of Georgia's breakaway region of Abkhazia, has died aged 62, Abkhaz officials say.
They say he passed away in a Moscow hospital from complications following recent lung surgery.
Mr Bagapsh won his second five-year term in 2009. Georgia denounced the elections as "illegitimate".
Since its brief war with Georgia in 2008 over another disputed territory, South Ossetia, Russia has provided security for Abkhazia.
Abkhazia declared independence from Georgia in 1992, but is only recognised by Moscow and a handful of other countries.
Abkhaz officials say Vice-President Alexander Ankvab will be acting leader.
Abkhazia had spun out of Georgia's control in fighting in the early 1990s. But during the 2008 war between Russia and Georgia, Abkhaz forces with help from the Russian military succeeded in pushing Georgian troops out of the last bit of territory they held in Abkhazia.
Moscow then recognized the independence of Abkhazia and South Ossetia, another separatist region and the focus of the brief war. Only Nicaragua, Venezuela and the small South Pacific island nation of Nauru have followed suit, while the rest of the world still considers both regions to be Georgian territory.
The following year, Bagapsh was re-elected to a second presidential term and vowed to maintain close ties with Russia.
Russia has thousands of troops based in Abkhazia and is deeply interested in the region's stability. It lies just to the south of Sochi, the Black Sea resort where Russia will host the 2014 Winter Olympics.
Russia's president and prime minister expressed their condolences to Abkhazians over the loss of Bagapsh, whom they praised for what they described as putting Abkhazia on the path to international recognition of its sovereignty and for strengthening ties with Russia.
A source in the Black Sea region's administration said Bagapsh underwent surgery in Moscow on May 21 and died of complications.
Alexander Ankvab, his deputy, has been appointed as acting president, with new elections required by the region's constitution within three months.
"We are deeply shocked by the death of Sergei Bagapsh," the acting head of Abkhazia told the Interfax news agency.
"This is a great loss for all the Abkhaz people," the acting leader said.
The region's security council was expected to meet later Sunday to discuss the situation.
There was no immediate official reaction to the news from Georgia, whose Western-backed President Mikheil Saakashvili is now facing almost daily street protests from pro-Russian opposition forces.
The acting leader Ankvab, 58, was born in Abkhazia and educated in Russia, according to his official biography.
He briefly served as interior minister after the Soviet Union's collapse before going into business and moving to Moscow for six years.
Ankvab served as prime minister between 2005 and 2010, and was appointed vice president in February 2010.