Renzi promised to resign if the public didn't support the overhaul of Italy's political system, which is intended to significantly reduce the number of lawmakers, allow laws to get passed quickly and stabilize future governments.
But if the vote goes against Renzi, and he keeps to his word of stepping down, then experts say it could have a more detrimental impact on the EU than Brexit.
"I made a mistake by personalizing it too much," he said at an event in the northern Italy city of Modena on Tuesday. "Italians need to know that this is not one person's reform, but a reform that will help Italy."
He also said that if the reform passes, then the government would be able to put the €500 million saved by cutting down on the number of lawmakers into the anti-poverty fund.
“How great it would be to put the savings towards our fellow citizens who struggle to make ends meet,” he said.
The referendum was given the go-ahead by the Court of Cassation on Monday. Renzi now has 60 days to set a date for the vote, which is likely to be held between October and December.