For decades there has been deep-seated dissatisfaction in the rich northern regions of Italy with what is widely regarded as inefficient and venal rule from Rome, as well as resentment that hard-won tax revenues are sent south and often squandered.
Around 3.8 million people in the Veneto are eligible to vote and campaigners hope to achieve a majority in favour of independence.
They want a future independent state to be known as "Repubblica Veneta" – in English the Republic of Veneto.
They acknowledge that the vote is not binding on the national government in Rome and could cause a massive constitutional upheaval, but insist that if it passes, they will start taking steps to withhold taxes, in what would effectively be a unilateral declaration of independence.
"If there is a majority yes vote, we have scholars drawing up a declaration of independence and there are businesses in the region who say they will begin paying taxes to local authorities instead of to Rome," Lodovico Pizzati, the spokesman for the independence movement, told The Telegraph.
"It won't be like in Scotland, where London has said it will recognise a vote in favour of independence. Rome has tried to ignore us, but we are not going to wait for their recognition.
"People are fed up with the economic crisis and have had it with Rome.
Scotland and Catalonia are way ahead of us, but the Veneto is very fertile ground – there has been an independence movement here since the 1970s," said Prof Pizzati, a former World Bank economist who currently teaches at California State University.
But many people in the Veneto are opposed to the idea of seceding from Italy. "It is anachronistic to think of a Europe made out of regions when we should strive for a Europe of stronger nations," said Pietro Piccinetti, the head of a committee campaigning for a no vote.
"We want to change, but within a stronger Italy."
By coincidence, the vote will take place on the same day as Crimea's referendum on independence from Ukraine.
"Venetians not only want out of Italy, but we also want out of the euro, the EU and Nato," said Raffaele Serafini, another pro-independence activist.
Like several other regions of Italy, the Veneto's ties with the rest of the country are fragile and of relatively recent origin.
After Napoleonic troops ended Venice's independence in 1797, the lagoon city was part of the Austrian empire for 60 years.
It was only in 1866 that it was annexed to the newly-unified Kingdom of Italy.