Thousands of Russian troops have taken control of the Black Sea peninsula, and Crimea's pro-Russian leaders have sought to ensure the vote is tilted in Moscow's favour. That, along with an ethnic Russian majority, is expected to result in a comfortable "Yes" vote to leave Ukraine, a move that could prompt US and European sanctions as early as today against those seen as responsible for the takeover of Crimea.
Provisional results were due late last night, with the final tally expected one or two days later.
At a polling booth inside a high school in Simferopol, the Crimean regional capital, turnout appeared to be high as people lined up to cast their ballots.
"I have voted for Russia," said Svetlana Vasilyeva, a veterinary nurse who is 27. "This is what we have been waiting for. We are one family and we want to live with our brothers.
"We want to leave Ukraine because Ukrainians told us that we are people of a lower kind. How can you stay in such a country?"
The majority of Crimea's 1.5 million electorate support leaving Ukraine and becoming part of Russia, citing expectations of better pay and the prospect of joining a country capable of asserting itself on the world stage. But others see the referendum as a geo-political land grab by the Kremlin which is seeking to exploit Ukraine's relative economic and military weakness as it moves towards the European mainstream.