Jo Johnson, the younger brother of Prime Minister Boris Johnson, is resigning as an MP and minister, saying he is “torn between family loyalty and the national interest”.
The business minister and Tory MP for Orpington, south-east London, cited an “unresolvable tension” in his role.
Mr Johnson voted Remain in the 2016 EU membership referendum, while his brother co-led the Leave campaign.
He resigned as a minister last year in protest at Theresa May’s Brexit deal.
But he re-entered government during the summer, after Conservative Party members elected his brother as leader.
A Downing Street spokesman said: “The prime minister would like to thank Jo Johnson for his service. He has been a brilliant, talented minister and a fantastic MP.
“The PM, as both a politician and brother, understands this will not have been an easy matter for Jo. The constituents of Orpington could not have asked for a better representative.”
BBC political editor Laura Kuenssberg said Mr Johnson’s resignation – following the removal of the Tory whip from 21 MPs this week for supporting moves to prevent a no-deal Brexit – showed “unbelievable timing”.
She added that Mr Johnson was “understood to be upset about the purge of colleagues”.