Taoiseach Enda Kenny has described the upcoming British referendum on European Union membership as the biggest decision for Ireland since the Good Friday Agreement.
He claimed Brexit would create instability and uncertainty, as well as the likely return of border checkpoints.
Mr Kenny said it was not credible to suggest nothing would change at the Irish border if the UK left the European Union.
"The re-establishment of customs checks on the border, or indeed of any customs arrangements, would be a regrettable and backward step for North-South trade and cooperation," he said.
In a speech in Belfast stressing the Government’s strong support for a Remain vote, Mr Kenny said, as the peace process came of age, people should take account of the "risks and challenges" that lay ahead.
"My address today is about what I firmly believe is the biggest challenge and the greatest risk - the forthcoming referendum on UK membership of the European Union," he said.
Mr Kenny added: "Later this month the people of Belfast, of Northern Ireland, of the UK as a whole, are being asked to make a momentous decision.
"That decision is as important for the future of this island as when we all voted for the Good Friday Agreement."
Mr Kenny said there was "no doubt" leaving the EU would involve changes to the trading rules between Britain and Ireland.
He said such a change would deliver "bad news" for the Northern Ireland economy.
"We are standing here today less than 50 miles from the United Kingdom's only land border," he told an audience at the University of Ulster.
"Can anyone credibly suggest that nothing would change if that became the western border of the European Union?
"We remember when it was a hard border. We remember the delays, the cost and the division.
"One of the most beneficial effects of the peace process and our common membership of the EU has been the virtual elimination of that border."
Mr Kenny said the decision on the future arrangements at the border would be up to the remaining 27 EU member states.
He said he would do his utmost to preserve the common travel area that allowed people to move freely.
But, in terms of trade, he said: "It is difficult to imagine a situation where there would be no controls or checks on the movement of goods if the UK left the EU.
"Those who advocate for Leave simply cannot guarantee otherwise."
He added: "No matter how successfully we negotiate any new arrangements, we all know that cannot be good for this island."
Mr Kenny said the continued stability of Northern Ireland depended on the continued success of the peace process and access to the support and markets the EU provided.
He said it was important to highlight the support the EU had given the peace process, both through funding and by providing a context through which the UK and Irish governments had built trust by working together on common goals.
The Taoiseach said the economies on both sides of the border would be negatively impacted if there was a Brexit.
"Continued membership of the European Union offers stability and certainty," he said.
"The alternative - by definition - cannot, does not and will not."
He noted he would be the only representative from Britain and Ireland at the European Council table.
"There will be nobody there - no voice at the most powerful table on our continent - to represent or speak for Britain, for Scotland, for Wales or for Northern Ireland," he said.
"That is why I am here today - to speak up for what I sincerely believe to be in the best interests of everyone on these islands."
He stressed the decision rested with the people of the UK.
"Nonetheless, it is no secret that the Irish Government very much wants the UK to stay as a member of the EU and work with us to make it better," he added.
"The prospect of Northern Ireland being outside the EU is one we very much wish to avoid."
Mr Kenny said whatever the outcome of the referendum, the Republic of Ireland would continue to be a "committed member" of the EU and of the Eurozone.
"Our position on that is clear and unambiguous," he said.
Labour to intensify opposition to Brexit
Meanwhile, former British prime minister Gordon Brown has compared the Brexit movement to the populist campaign of US presidential candidate Donald Trump, as Labour launched a drive to persuade its supporters to vote to Remain in the 23 June referendum.
The former prime minister accused the Leave campaign of seeking a return to an outdated Victorian conception of sovereignty, which he said would be a "huge disaster" for jobs and the economy.
But his intervention was dismissed as a sign of "panic" by leading Leave campaigner Boris Johnson, who said Mr Brown was to blame for relaxing immigration controls while in power.
With 10 days to go before Britain decides whether to end its 43-year membership of the EU, opposition figures are being thrust centre-stage by concerns that growing numbers of Labour voters may be considering a Leave vote.
Pro-EU leaders are concerned that this potentially pivotal group has been pushed towards Brexit by the campaign's focus on Tory rivalries and immigration as well as uncertainties over leader Jeremy Corbyn's commitment to the EU cause.