Justice Minister Dermot Ahern said today substantial referendum returns showed that Ireland had rejected the European Union reform treaty.
Electoral officials expect to confirm the result later today.
The second constitency to announce official results was Sligo-North Leitrim, which returned a No vote by 56.7% to 43.3%.
Mr Ahern based his conclusion on tallies of votes produced nationally by election observers as well as early official returns.
They showed the No camp ahead in the vast majority of Ireland’s 43 electoral constituencies, while pro-treaty voters were clearly ahead in only a few.
The expected result will send shockwaves throughout the EU.
Ireland was the only member to subject the Lisbon Treaty to a popular vote, while other countries have been ratifying the painstakingly negotiated pact only through their national governments.
Mr Ahern said: “We’re in uncharted waters.”
“Based on the unofficial early figures it's not looking too good for the Yes side.
“It’s still all unofficial but the indications are that the No side could win.”
A spokesman for Mr Ahern stressed that he was not conceding defeat at this stage as counting continued throughout the country.