Voters in Ireland have rejected the European Union's Lisbon reform treaty in a referendum by 53.4% to 46.6%.
The vote is a major blow to leaders in the 27-nation EU, which requires all its members to ratify the treaty.
Only Ireland has held a public vote.
The European Commission has already said other nations should continue to ratify the treaty, which is designed to streamline decision-making.
Leaders of the No campaign said the vote was a "great result for Ireland".
An earlier, more wide-ranging EU draft constitution failed after French and Dutch voters rejected it in 2005.
'Uncharted waters'
The Irish No campaign won by 862,415 votes to 752,451. Turnout was 53.1%.
Ahead of the result, Irish Justice Minister Dermot Ahern said the expected No vote would leave the EU in "uncharted waters".
Finance Minister Brian Lenihan said: "I'm very, very disappointed by this result. I think it's a sad day for Europe and for our people as well."
A referendum was mandatory in Ireland as the country would need to change its constitution to accommodate the treaty.
European Commission President Jose Manuel Barroso said he had spoken to Irish Prime Minister Brian Cowen and agreed with him that this was not a vote against the EU.
"Ireland remains committed to a strong Europe," he said.
"Ratifications should continue to take their course."
France and Germany quickly issued a joint statement expressing regret over the Irish result.
Spain has said a solution will be found but Czech President Vaclav Klaus said ratification could not now continue.
Mr Barroso said EU leaders would have to decide at a summit next week how to proceed.
He called for the EU to continue focusing on issues of interest to people like jobs and inflation, energy security and climate change.
However, the BBC's Oana Lungescu in Brussels says the third failed referendum on an EU treaty in three years only points to the growing gap between people and their leaders.
European leaders earlier said they had no "plan B" for how to proceed if Ireland's electorate voted No.
Declan Ganley of the anti-treaty lobby group Libertas said it was a "great day to be Irish".
"The people of Ireland have shown enormous courage and wisdom in analysing the facts presented to them and making the decision they have," Mr Ganley said.
The No campaign was a broad coalition ranging from Libertas to Sinn Fein, the only party in parliament to oppose the treaty.
Gerry Adams, the president of Sinn Fein, said: "People feel secure at the heart of Europe, but they want to ensure there's maximum democratic power."
Confusion
Correspondents say many voters did not understand the treaty despite a high-profile campaign led by Mr Cowen, which had the support of most of the country's main parties.
Mr Cowen accused the No camp of "misrepresentation", saying voters had voiced concern about "issues that clearly weren't in the treaty at all", the Irish Times reported.
The treaty, which is designed to help the EU cope with its expansion into eastern Europe, provides for a streamlining of the European Commission, the removal of the national veto in more policy areas, a new president of the European Council and a strengthened foreign affairs post.
The treaty was due to come into force on 1 January 2009.
Fourteen countries out of the 27 have completed ratification so far.
Just over three million Irish voters are registered - in a European Union of 490 million people.
(BBC)
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