Parliament voted 432-202 against her deal, the worst parliamentary defeat for a government in recent British history.
Scores of her own MPs – both Brexiteers and supporters of EU membership – joined forces to vote down the deal on Tuesday night.
Opposition Labour leader Jeremy Corbyn promptly called a vote of no confidence in May’s government, to be held within 24 hours.
With the clock ticking down to March 29, the date set in law for Brexit, the UK is now ensnared in the deepest political crisis in half a century as it grapples with how, or even whether, to exit the European project that it joined in 1973.
May’s crushing loss, the first British parliamentary defeat of a treaty since 1864, marks the collapse of her two-year strategy of forging an amicable divorce with close ties to the EU after the March 29 exit.
“It is clear that the House does not support this deal, but tonight’s vote tells us nothing about what it does support,” May told parliament, moments after the result was announced.
“We need to confirm whether this government still enjoys the confidence of this House,” May said.
May said parliament had spoken and the government had listened.
The small Northern Irish DUP party, which props up her minority government and had said it would oppose the deal, said it would still back May in the no confidence vote.
The EU said the Brexit deal remained the best and only way to ensure an orderly withdrawal from the EU.
“The Brexit deal is basically dead,” said Anand Menon, professor of European politics and foreign affairs at King’s College London.
Ever since Britain voted by 52-48 per cent to leave the EU in a referendum in June 2016, the political class has been debating how to leave the European project forged by France and Germany after the devastation of World War Two.
While the country is divided over EU membership, most agree that the world’s fifth-largest economy is at a crossroads and that its choices over Brexit will shape the prosperity of future generations.
Before the vote, May had warned pro-Brexit MPs that if her plan was rejected, it was more likely that Britain would not leave the EU at all than that it would leave without a deal.
She has also warned fellow Conservatives not to let the opposition Labour Party seize control of Brexit.
Supporters of EU membership cast Brexit as a gigantic mistake that will undermine the West, smash Britain’s reputation as a stable destination for investment and slowly weaken London’s position as a global capital.
Many opponents of Brexit hope May’s defeat will ultimately lead to another referendum on EU membership, though Brexiteers say that thwarting the will of the 17.4 million who voted for Brexit could radicalise much of the electorate.
Brexit supporters cast leaving as a way to break free from a Union they see as overly bureaucratic and fast falling behind the leading economic powers of the 21st century, the United States and China.
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