Italian Prime Minister Matteo Renzi has resigned after suffering a heavy defeat in a referendum over his plan to reform the constitution.
In a late-night statement, he said he took responsibility for the outcome.
He said the No camp must now make clear proposals.
An exit poll for state broadcaster RAI suggests 42-46% voted to back reform, compared with 54-58% voting No.
The first projections based on the official count point to a wider defeat.
Early indications have the Yes vote at 39-43% and the No at 57-61%.
The referendum was regarded as a barometer of anti-establishment sentiment in Europe.
The vote asked about plans to streamline parliament but it was widely seen as a chance to register discontent with the prime minister.
Populist parties supported a No vote.
Opposition leader Matteo Salvini, of the anti-immigrant Northern League, said that if the exit polls were confirmed, the referendum will be a “victory of the people against the strong powers of three-quarters of the world”.
The euro fell against the dollar immediately after the exit polls came out.
There have been growing concerns over financial stability in the eurozone’s third largest economy.
There has been an immediate reaction from right-wing leaders in Europe.
The leader of Front Nationale in France, Marine Le Pen, tweeted her congratulations to the Northern League.
“The Italians have disavowed the EU and Renzi. We must listen to this thirst for freedom of nations,” she said.
The turnout was very high by Italian standards – about 60% of the electorate cast their vote.
Nearly two-thirds voted in prosperous northern Italy but the turnout was much lower in the south.
What a No vote means
The No campaign in Italy has been spearheaded by the anti-establishment Five Star Movement, led by Beppe Grillo.
It wants a referendum on whether Italy should keep the euro.
The projections, if they are right, will give a boost to populist parties, including the Five Star Movement and the anti-immigrant Northern League.
The referendum comes in the wake of the Brexit vote in the UK in June, and coincides with the rise of the anti-immigrant Front National in France and populist parties elsewhere. It also comes less than a month after the election of Donald Trump in the United States.
Some 50 million Italians have the right to vote in the referendum – many voters are fed up with years of economic stagnation.