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Karimov earned degrees in engineering and economics from the Central Asian Polytechnic and the Tashkent Institute of National Economy. Later he became a member of the Academy of Sciences in Uzbekistan. He worked first as an aircraft engineer (1961–66) before entering government employment in 1966 as an economic planner for the Uzbek state planning office.

Karimov became first secretary of the Communist Party of Uzbekistan in 1989 and was elected president of the Uzbek Soviet Socialist Republic in 1990. After the collapse of the Soviet Union in 1991, he was elected president of independent Uzbekistan. In 1995 a national referendum extended his presidency to 2000, when he was reelected to another five-year term. In 2002 another national referendum extended his presidency to 2007. Although the Uzbek constitution prohibits presidents from serving more than two terms in office, Karimov was elected to a third term in 2007. The international community largely agreed that the elections that had placed Karimov in office were neither free nor fair. Karimov won another term in 2015 amid similar concerns regarding the fairness of elections.

Karimov was accused of stifling political opposition and sanctioning widespread human rights abuses in his country. Despite such criticism, he became an ally of the United States after the 2001 September 11 attacks and granted basing rights to U.S. forces operating in Afghanistan in exchange for military and economic assistance. Karimov was also supported by the Russian government.

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On August 29, 2016, one of Karimov’s daughters, Lola Karimova-Tillyayeva, announced over social media that her father had been hospitalized for a cerebral hemorrhage. Karimov’s health crisis set off a round of speculation about who would succeed him as president. There were also unconfirmed reports that he had actually died but that the news was being held back by members of his inner circle. On September 2 the government officially confirmed Karimov’s death. A funeral was held the next day in Samarkand, and the prime minister, Shavkat Mirziyoyev, took over as acting president.