Premier Matteo Renzi has said he will resign if the reforms are rejected, and opposition politicians have vowed to press for a new government if voters reject the proposed constitutional changes.
The premier made no comment as he voted today in Pontassieve, a Tuscan town east of Florence, along with his wife, Agnese Landini. He was to return to Rome to watch the outcome of the vote.
The risk of political instability in Italy, Europe's fourth-largest economy, triggered market reaction before the vote, with bank stocks sinking and borrowing costs on sovereign debt rising.
The referendum in Italy aims to streamline Italy's cumbersome lawmaking process by reducing the powers of the Senate, while also removing some key decision-making powers from regions.
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Renzi has argued that the reforms dismantle bureaucracy and will make Italy more attractive to investors and will help him relaunch the country's moribund economy. But his decision to tie the outcome to his political future turned the vote into a plebiscite on his leadership.
The Guardian newspaper noted that the referendum was among a series of votes in Europe that could "conceivably herald the end of the European project in its current form."
Some political opponents were hoping to tap populist sentiment that has been gaining ground with the UK vote in June to leave the European Union and the US presidential victory last month by billionaire political outsider Donald Trump.
More than 46 million Italians were eligible to cast votes while another 4 million were registered to vote abroad. The overseas votes were being tallied under guard at a warehouse outside of Rome.
Three former premiers -- Silvio Berlusconi, Massimo D'Alema and Mario Monti -- have come out against the reforms for different reasons.
Berlusconi has argued that it concentrates too much power in the premier, while Monti says the reforms don't go far enough.
How the vote plays out politically is likely to depend on the turnout and the margin of the decision.