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Sajid Javid has said he cannot "risk my integrity" by continuing to defend the government, telling Boris Johnson "enough is enough".
MPs, including Mr Johnson, listened in silence as he set out the reasons for his resignation as health secretary.
"It is incumbent on all of us to set high standards for ourselves and to take action when they are not met by others," Mr Javid told MPs.
He said he could not go on giving Number 10 the "benefit of the doubt".
Chancellor Rishi Sunak announced his own departure from government within minutes of the former health secretary, on Tuesday evening, and they have been followed out the door by a string of junior ministers.
Mr Johnson batted away calls to stand down at Prime Minister's Questions, saying he intended to "get on with the job" of governing, to howls of protest from the opposition benches.
But MPs fell silent as Mr Javid got to his feet to deliver his resignation statement.
He told the Commons: "I also believe a team is as good as its team captain and a captain is as good as his or her team. So, loyalty must go both ways.
"The events of recent months have made it increasingly difficult to be in that team.
"It's not fair on ministerial colleagues to go out every morning defending lines that don't stand up and don't hold up.
"It's not fair on my parliamentary colleagues, who bear the brunt of constituents' dismay in their inboxes and on the doorsteps in recent elections.
"And it's not fair on Conservative members and voters who rightly expect better standards from the party they supported."
In an apparent message to members of the Cabinet who have stayed, he said: "Not doing something is an active decision".
He told MPs: "Last month I gave the benefit of doubt one last time... I have concluded that the problem starts at the top and I believe that is not going to change and that means that it is for those of us in a position who have responsibility to make that change.
"I wish my Cabinet colleagues well and I can see they have decided to remain in the Cabinet. They will have their own reasons."
Laughter could be heard in the chamber, as Mr Javid went on: "But it is a choice. I know just how difficult that choice is. But let's be clear, not doing something is an active decision."