MPs have rejected Theresa May’s EU withdrawal agreement on the day the UK was due to leave the EU.
The government lost by 344 votes to 286, a majority of 58.
It means the UK has missed an EU deadline to delay Brexit to 22 May and leave with a deal.
The prime minister said the UK would have to find “an alternative way forward”, which was “almost certain” to involve holding European elections.
Mrs May now has until 12 April to seek a longer extension to the negotiation process to avoid a no-deal Brexit on that date.
With a clear majority in the Commons against a no-deal Brexit, and with MPs holding more votes on alternative plans on Monday, Mrs May said that the UK would have to find “an alternative way forward”.
The prime minister said that the outcome was “a matter of profound regret”, adding that “I fear we are reaching the limits of this process in this House”.
Responding to the vote, European Council President Donald Tusk tweeted: “In view of the rejection of the Withdrawal Agreement by the House of Commons, I have decided to call a European Council on 10 April.”
Steve Baker, deputy chairman of the European Research Group of Brexiteer Conservatives, said it was time for Mrs May to quit.
“This must be the final defeat for Theresa May’s deal. It’s finished. And we must move on.
“It has not passed. It will not pass. I regret to say it is time for Theresa May to follow through on her words and make way so that a new leader can deliver a withdrawal agreement which will be passed by Parliament.”
Mr Baker was one of 34 Conservative rebels to vote against the agreement, along with the Democratic Unionist Party and the Labour Party. Five Labour MPs voted for the agreement.
A number of high profile Tory Brexiteers, including Dominic Raab and Iain Duncan Smith, did vote for the agreement, but it was not enough to prevent another damaging defeat for Mrs May, who had offered to stand down to persuade her critics to back the deal.
This was not a third “meaningful vote” on the PM’s EU deal, which also includes a political declaration on future relations between the UK and the EU, and which has previously been rejected by larger margins.
By holding a vote on the withdrawal agreement only, the government had hoped to secure a short delay to Brexit and avoid the UK taking part in May’s European elections.
MPs are set to have another go at reaching a Brexit compromise in another series of votes on Monday and Wednesday next week.
If one of the options receives a majority, the government could use it as a basis for negotiating changes to the political declaration.
Labour leader Jeremy Corbyn said: “The House has been clear, this deal now has to change.
“There has to be an alternative found. And if the prime minister can’t accept that then she must go, not at an indeterminate date in the future but now.
“So that we can decide the future of this country through a general election.”