Brexit negotiator Lord Frost has resigned from government after opposing the prime minister's Plan B coronavirus restrictions.
The peer, formerly a member of Boris Johnson's Cabinet, said he would leave his post with "immediate effect" after previously being persuaded to stay on until January.
He is said to have become disillusioned by tax rises and the cost of net zero policies.
In a letter sent to PM, he wrote: "I have led our EU exit process for the two and a half years since you became Prime Minister. In those years we have restored the UK's freedom and independence as a country and begun the process of building a new relationship with the EU. That will be a long term task.
"That is why we agreed earlier this month that I would move on in January and hand over the baton to others to manage our future relationship with the EU.
"It is disappointing that this plan has become public this evening and in the circumstances I think it is right for me to write to step down with immediate effect."
Despite the differences with No10, it is believed the departure is “on good terms”.
Lord Frost has recently been locked in tense rounds of talks with European Commission vice-president Maros Sefcovic as the UK and the EU attempt to close gaps in post-Brexit arrangements.
Labour's deputy leader Angela Rayner said the news represented "a government in total chaos right when the country faces an uncertain few weeks".
She tweeted: "@BorisJohnson isn't up to the job. We deserve better than this buffoonery."
Liberal Democrat foreign affairs spokesperson Layla Moran said: "This shock resignation is a sign of the chaos and confusion at the heart of this Conservative government.
"The rats are fleeing Boris Johnson's sinking ship as he lurches from crisis to crisis.
"Even the prime minister's once-loyal supporters are now abandoning him, just as lifelong Conservative voters are switching in their droves to the Liberal Democrats.
"At a time we need strong leadership to get us through the pandemic, we instead have a weak Prime Minister who has lost the support of his allies and the trust of the British people."
Northern Ireland's former first minister Arlene Foster described Lord Frost's resignation as "enormous".
In a tweet, she said: "The resignation of Lord Frost from the Cabinet is a big moment for the Government but enormous for those of us who believed he would deliver for NI."
News of his resignation came amid speculation that even tighter restrictions are about to be announced for the UK in response to the fast-spreading Omicron variant of Covid.
The PM, keen for this Christmas to be better than last, has so far resisted calls to tighten Covid restrictions but his scientific advisers have told him further intervention is needed to keep hospital admissions down.The UK is experiencing a fresh wave of Covid, caused by the fast-spreading Omicron variant, with daily coronavirus cases over 90,000 for the second day running after the highest ever daily total of 93,045 was recorded Friday.
Another six Omicron deaths have also been reported, meaning seven people in the UK have now died with the variant, while the addition of 10,059 further infections brings the total number of confirmed Omicron cases to 24,968.
And major incident was declared in London after the capital recorded its highest ever daily increase of Covid cases on Saturday.
Documents released by the Scientific Advisory Group for Emergencies (Sage) on Saturday showed the government was being told on Thursday that hospitalisations will soon reach at least 3,000 a day without tighter restrictions.
"If the aim is to reduce the levels of infection in the population and prevent hospitalisations reaching these levels, more stringent measures would need to be implemented very soon," the scientists told ministers.