"To be brief: If the UK leaves Europe, it is forever," Renzi said at the Saint Petersburg Economic Forum alongside President Vladimir Putin.
In a football metaphor, he added that with this referendum, "it's not that there is first a home match and then an away game."
The Italian premier added in comments translated into Russian that "if (Brexit) happens, in the short term, it will primarily be a big problem for the British, not for Europeans."
"At least in the initial stages, I think there will be very serious financial strains," he warned.
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He predicted nevertheless that British people would choose to stay in the European Union despite some polls suggesting a victory for the Brexit camp.
"I think victory will be claimed by those who want to stay in Europe," he said. "I believe that the British are much wiser than what we see in polls."
He said that whatever the result of the referendum, the European Union must reform itself. "This Europe based on austerity, it doesn't work.