Conservative co-chair Oliver Dowden has resigned following two by-election losses for the party to Labour and the Liberal Democrats.
The Lib Dems overturned a huge Tory majority in Tiverton and Honiton, Devon, their third by-election victory over Boris Johnson's party in a year.
And Labour retook the seat of Wakefield, West Yorkshire, which it lost at the 2019 general election.
The prime minister said he would "keep going" and address people's concerns.
In a letter to Mr Johnson, Mr Dowden said Tory supporters were "distressed and disappointed".
He wrote: "We cannot carry on with business as usual. Somebody must take responsibility and I have concluded that, in these circumstances, it would not be right for me to remain in office."
Mr Dowden also called his resignation "a deeply personal decision that I have taken alone" following a "run of very poor results for our party".
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