The vote, which echoes the rise of populism in Europe and the United States, will shape the future of Europe and the West. A victory for "out" could unleash turmoil on financial markets.
"It's very close; nobody knows what's going to happen," Cameron told the Financial Times, with opinion polls showing the rival camps neck and neck.
Thursday's vote comes just a week after the murder of MP Jo Cox shocked the country, raising questions about the tone of a campaign that has become increasingly bitter.
The EU - already shaken by differences over migration and the future of the euro zone - would lose its second-largest economy if Britons vote yes to leave, one of its top two military powers and by far its richest financial centre.
In the last major debate of the referendum, London's mayor Sadiq Khan accused Boris Johnson, the main leader of the Leave campaign, of orchestrating "project hate" and exploiting fears of immigration to stoke anti-EU opinions.
"Your campaign hasn't been 'project fear', it's been 'project hate' as far as immigration is concerned," Khan said to huge applause from the 6000 crowd at a live TV debate at London's Wembley Arena on Tuesday night.
"This Thursday can be our country's independence day," Johnson, seen as a leading contender to replace Cameron if Leave wins, told the cheering audience in a venue more often used to stage rock concerts.
Johnson, Khan's Conservative predecessor as mayor of London, said the Remain camp spoke of nothing but fear and were "rubbishing" Britain. He will travel across Britain in a helicopter on Wednesday in the race to mobilise voters.
In a campaign marked by warnings of economic devastation if Britain leaves and of uncontrolled immigration if it stays in the EU, polls have painted a contradictory picture of public opinion in a deeply divided nation.
Since Cox's murder some polls have given a slight lead to Remain, often within the margin of error.
The implied probability of a Remain vote was at 75%, according to Betfair odds, while the pound edged back to $US1.4681 after climbing to as high as $US1.4788 on Tuesday, its highest level since January 4.
Polling stations open at 6am (local time) on Thursday and close at 9pm. The official result is due some time after 6am on Friday (local time) but partial results and turnout figures from 382 counting centres will be announced from about 1am.
World leaders including US President Barack Obama, Chinese President Xi Jinping, German Chancellor Angela Merkel and the NATO and Commonwealth allies have all urged Britain to remain in the EU and some have warned of the drawbacks of isolation.
France's government spokesman said on Wednesday that Britain would lose access to the EU's prized single market if it voted to quit and ceased paying into the common budget.
PM's fate hangs on decision
Cameron, who called the referendum under pressure in his own Conservative party and from the insurgent UK Independence Party, made an unscheduled solemn appearance outside his Downing Street residence on Tuesday to appeal to voters to remain in the club it joined in 1973.
"Brits don't quit," he said, using the official backdrop to make a direct pitch to older voters considered more eurosceptic and more likely to vote.
His fate hangs on the result. A vote to leave would almost certainly lead to his exit from the top job, though he has insisted he will stay. But even a narrow vote to remain could undermine his authority and shorten his term.
The bosses of 51 of the FTSE 100 British companies, and 1285 business leaders who together employ 1.75 million people, signed a joint letter to The Times urging voters to remain.
"Britain leaving the EU would mean uncertainty for our firms, less trade with Europe and fewer jobs," they said. "Britain remaining in the EU would mean the opposite: more certainty, more trade and more jobs."
A vote to leave would unleash turmoil on foreign exchange, equity and bond markets, lead to a political crisis in Britain and fragment the post-Cold War European order.
The EU would have to weather the exit of its No 2 economy representing $US2.9 trillion ($NZ 4 trillion) of its gross domestic product, the only European financial capital to rival New York and one of its only two nuclear powers, while Britain's economy could stall.
A vote to remain would trigger a rise in sterling and relief in Western capitals, unleash pent-up investment in Britain but still leave the country - and the Conservatives - bitterly divided, especially if the margin of victory was thin.
Investment bank Citi estimated in a research note there was a 60% chance Britons would vote to stay in the EU but said a "close remain" could still undermine political stability in both the United Kingdom and the 28-member bloc.
"A vote to 'Leave' would have major repercussions in global financial markets, the economy and politics, triggering substantial downward revisions of UK and European growth forecasts," Citi said.
