The online vote, organized by local independence parties, is not legally binding but aims to galvanize support for a bill calling for a referendum on whether the region of Veneto should split from Italy.
The new Republic of Veneto would be inspired by the ancient Venetian republic - a rich economic, cultural and trading power which existed from the 7th century until its fall to Napoleon in 1797.
The Indipendenza Veneta party behind the bill said the separatist movement was fuelled by the government's apparent inability to stamp down on corruption, protect its citizens from a damaging recession and plug waste in the poorer south.
"We no longer want to be part of a country that has gone to the wall. Nothing works anymore," Nicola Gardin from the party said.
"Italy is weighed down by an enormous level of public debt, thousands of businesses have closed, we have lost count of the number of people who have committed suicide in Veneto," he said.
The region pays around €71 billion in taxes to Rome, €21 billion more than it receives in investment and services.
The latest polls show that - of the 3.8 million people eligible to vote in the region - around 60 percent is in favour of independence.
Despite protests that any attempt to split from Italy would be unconstitutional, the governor of the Veneto region Luca Zaia has told Italian media that secession is an option under international law.
Venetians will be closely watching independence movements in Scotland - which will hold a referendum in September - and Catalonia, he said.
"If Barcelona gets independence, Veneto could adopt the same method and get it too. We have knocked politely on the door of federalism, but it did not open. Now we will break down the door," he said.
Organizers of the online poll, which closes on Friday, said they expected up to two million voters to take part. A large independence demonstration is then planned in Padova on Sunday, expected to draw hundreds of thousands of people.
"The history of the Venetian republic is not taught in schools any more, neither is the Venetian language. The state has erased our identity," Gardin said.
"The vote for independence is not just driven by economic reasons, it is also a bid to protect and revive our culture," he said.