MPs have backed seeking "alternative arrangements" to replace the Irish backstop in Theresa May's Brexit plan.
The proposal - put forward by Tory MP Sir Graham Brady - had the support of the government and won by 16 votes.
Theresa May had urged MPs to vote in favour of it, to give her a mandate to return to Brussels and re-open negotiations in order to secure a "legally binding change".
But the EU has said it will not change the legal text agreed with the UK PM.
MPs voted on a string of amendments to Mrs May's plan to change the direction of Brexit.
Mrs May said that, after taking the votes into account and talking to the EU, her revised deal would be brought back to the Commons "as soon as possible" for a second "meaningful vote".
Another amendment, rejecting a no-deal Brexit, also won the support of Parliament today, but the vote was not binding - meaning the date for exit remains 29 March.
Labour leader Jeremy Corbyn said as a result of the message from MPs rejecting no deal, he would now meet the prime minister to discuss the next steps.
He had previously refused to meet her unless she ruled out a no-deal Brexit herself.
Mr Corbyn said: "After months of refusing to take the chaos of no deal off the table, the prime minister must now face the reality that no deal is not an option."
Five other amendments, including Labour MP Yvette Cooper's bid to delay Brexit if Mrs May does not get her deal through Parliament, were defeated.
Tory MP Nick Boles, who worked with her on the amendment, tweeted out a joint statement, saying they "remain deeply concerned that there is no safeguard in place" to stop a no deal and said Mrs May's revised plan would have to "reflect the Commons opposition to no deal".
Mrs May hopes the support for Sir Graham's amendment - which won by 317 votes to 301 - to look at alternatives to the backstop gives her a stronger negotiating position with the EU.
The contentious element of Mrs May's original plan is the insurance policy to prevent checks on goods and people returning to the Northern Ireland border with the Irish Republic.
It would effectively keep the UK inside the EU's customs union, but with Northern Ireland also conforming to some rules of the single market.
It was one of the main reasons her Brexit deal was voted down in Parliament by an historic margin earlier in January as critics say a different status for Northern Ireland could threaten the existence of the United Kingdom and fear that the backstop could become permanent.
She told the Commons there was now a "substantial and sustainable" majority of MPs supporting leaving the EU with a deal, but admitted renegotiation "will not be easy".
The leader of the Democratic Unionist Party in Westminster, Nigel Dodds, said it was a "significant night" and his MPs would work with the prime minister "to deliver the right deal for the United Kingdom".
But the leader of the SNP in Westminster, Ian Blackford, said that passing the amendment had seen the government "rip up the Good Friday Agreement" - integral to the peace process in Northern Ireland.
Liberal Democrat leader Sir Vince Cable said the Commons had given the prime minister "contradictory instructions to have no deal but pursue a course of action that will lead to a no deal".