More than three-quarters of Greek Cypriots have voted against a UN plan to reunite the island in a referendum.
Many Greek Cypriots are sceptical about the UN plan
Turkish Cypriots, in contrast, endorsed the plan with a 65% majority, according to official results.
But both sides had to approve the proposals for Cyprus to be reunified in time for EU membership on 1 May.
UN envoy to Cyprus Alvaro de Soto "regretted" the rejection of the plan. The UN also announced it was closing down the peace envoy's office.
The US said it was "disappointed" with the result which was a "setback to the hopes of those on the island who voted for the settlement and to the international community".
The European Commission also said it regretted the Greek Cypriot rejection, which means EU laws and benefits will now apply only to their community.
"A unique opportunity to bring about a solution to the long-lasting Cyprus issue has been missed," the Commission said in a statement.
It congratulated Turkish Cypriots for their endorsement and promised to "consider ways of further promoting economic development of the northern part of Cyprus".
Official results showed 75.8% of Greek Cypriots voted against the reunification plan. Turnout was 89%.
The result is no surprise, says the BBC's Tabitha Morgan in Nicosia.
For days the only uncertainty has been the size of the 'no' vote - Greek Cypriots rejected the deal by a far larger margin than had been expected, our correspondent says.
Diplomats had expressed concerns that a Greek veto would put paid to years of international pressure to reconcile the two parts of the island, split since the 1974 invasion by Turkish troops.
They had expressed hopes that the deal would be rejected by only a narrow margin and that the same plan might be put to the people once again in a few months' time.
The nature of the result appears to rule this possibility out, our correspondent says.
Greek Cypriot President Tassos Papadopoulos, who urged voters to reject the plan, said he remained committed to reaching a deal with the north.
"Today's result must act as a catalyst for reunification, and not used as an excuse for further division," he said.
But hardline Turkish Cypriot leader, Rauf Denktash - a fierce opponent of the UN plan - called on the world to stop pressing the two sides to live together.
"There must be no uncertainty caused by futile attempts to force incompatible parties together," Mr Denktash said.
His Prime Minister Mehmet Ali Talat - a supporter of the plan - called on the UN and the EU to take measures to redress the irony that the side that rejected the plan gets to become an EU member in a week's time.
Mr Talat said the isolation of northern Cyprus must be ended or alleviated - a call echoed by Turkey.
"The embargoes must be lifted, the isolation must be brought to an end," said in Ankara Turkey's Foreign Minister Abdullah Gul.
After this vote, he said, Turkey would not pull out its 30,000 troops.
The plan crafted by UN Secretary-General Kofi Annan envisages a loose federal structure for the island.
Many Greek Cypriots refugees who fled the Turkish assault would be allowed to return and recover some of the land they lost.
But the Greek side is unhappy that the plan limits their right to return, while allowing tens of thousands of Turkish settlers introduced since 1974 to remain.
Turkish troops would also be allowed to maintain a reduced garrison on the island.