Announcing her resignation, Work and Pensions Secretary Esther McVey said the Brexit deal "does not honour the result of the referendum".
It comes after Brexit Secretary Dominic Raab also resigned over the plan to leave the EU.
Ms McVey claimed she couldn't look voters in the eye if she sold out Brexit by backing a plan which leaves Britain "trapped in a customs union".
In a letter to Theresa May, she wrote: "The deal you put before the Cabinet yesterday does not honour the result of the referendum. Indeed, it doesn't meet the tests you set from the outset of your premiership."
She added: "We have gone from no deal is better than a bad deal, to any deal is better than no deal."
The lengthy letter added she had "no alternative but to resign from the Government."
Mr Raab said he couldn't support Mrs May's Brexit deal because it breaks the promises she made to the country.
He told The Sun: "I don’t want to submit to the blackmail of my country."
Mr Raab is the second Brexit Secretary to quit in just four months – after David Davis walked out in protest at the PM's Chequers plans.
Suella Braverman has also resigned as a Brexit minister, her office announced today.
Anne-Marie Trevelyan also tendered her resignation as a parliamentary private secretary in the Department for Education, saying she cannot support the Brexit deal after negotiations “built on the UK trying to appease the EU”.
Unconfirmed reports claimed International Development Secretary Penny Mordaunt was also set to resign today.
And Michael Gove, one of the Cabinet's key Brexiteers, has cancelled a planned visit to a conference in Yorkshire.
Mr Raab wrote: "I cannot support the proposed deal for two reasons. First I believe that the regulatory regime proposed for Northern Ireland presents a very real threat to the integrity of the United Kingdom.
"Second, I cannot support an indefinite backstop arrangement, where the EU holds a veto over our ability to exit."
But he insisted he has "enduring respect" for Mrs May and praised the PM for fighting through "difficult times".
Despite claiming he is not launching a leadership bid, bookies immediately made him favourite to take over from Mrs May if she is forced out as Tory leader.
The pound plunged after Mr Raab's resignation as fear grew that Mrs May would be unable to force ANY deal through the House of Commons.
Mrs May will face down dozens of rebellious Tories in a desperate bid to save her Brexit deal and her job.
The PM’s former chief of staff Nick Timothy last night issued a scathing attack on her to claim she NEVER thought Brexit could succeed.
Mr Timothy, who resigned after the 2017 election disaster, also branded her Brexit divorce deal a “capitulation”.
More to follow…
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