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Votes against creditors' bailout terms are in the lead by 60.64 percent "no" to 39.36 per cent "yes."
Speaking before the announcement of the first official results, lead negotiator Tsakalotos indicated that Athens could immediately resume discussions with its creditors.
"We are ready from tonight to meet (with creditors) for a deal," said Tsakalotos, in an interview with Greek Star TV, and emphasized that a new deal should address the issue of debt.
The referendum asks Greeks whether they approve of the bailout conditions offered before Athens stopped talks with the country's creditors - the European Commission, the European Central Bank(ECB)and the International Monetary Fund (IMF).
It was taking place at the end of a tumultuous week that saw banks close, a cap on cash withdrawals and a failure to repay an IMF loan.
Fears are rife that Greece could become the first country to be ejected from the eurozone, and the referendum is widely perceived as a vote on whether the country should remain in the bloc or not.
Prior to the result, a German government spokesman announced that German Chancellor Angela Merkel would meet with French President Francois Hollande in Paris on Monday to discuss the results of the referendum.
The talks due to begin at 6:30 pm (1630 GMT) and continue through a working dinner are to centre around close Franco-German cooperation in light of the Greek result.
A series of opinion polls ahead of the referendum showed a tight race, with a slim lead for the "yes" camp that is well within the margin of error. The polls also showed an overwhelming majority of people want Greece to remain in the eurozone.
"For them to cut my pension? No," one pensioner, who declined to give her name, told dpa outside a polling station in Thissio in central Athens.
Vasilios Mantelas, 65, said he deliberately cast an invalid vote. "I want Greece out of the European Union and out of memorandums," he said, referring to the bailout programmes.
Sofia Alexiou, 39, who voted "no" at Metaxourgeio in Athens, said: "This is a 'no' to the blackmail of Greek and European elites."
The referendum also serves as a nationwide vote of confidence in Tsipras' government, which came to power in January on an anti-austerity ticket. Analysts say he will have no choice but to resign if the "yes" vote wins.
Outside of Greece, UKIP party leader Nigel Farage was one of the first to comment on the referendum.
"If these poll figures are correct, I commend the Greek people for calling the EU's bluff," he said.
"The EU project is now dying. It's fantastic to see the courage of the Greek people in the face of political and economic bullying from Brussels."
The Bank of Greece was expected later Sunday to request an increase in liquidity through the ECB's Emergency Liquidity Assistance (ELA), according to Greek TV Mega.
With Greece on the brink of insolvency amid inconclusive talks with its creditors, the ELA has been helping the Greek central bank provide liquidity to commercial banks.