Chancellor Rishi Sunak and Health Secretary Sajid Javid have resigned from government saying they no longer have confidence in Boris Johnson to lead the country.
The resignations came minutes after PM sought to draw a line under a row about MP Chris Pincher, who is facing sexual misconduct allegations.
Mr Johnson admitted he had made a "bad mistake" in appointing Mr Pincher to the role of deputy chief whip earlier this year, despite being told about earlier allegations about the MP's conduct.
Asked if that was an error to appoint Mr Pincher, Mr Johnson said: "I think it was a mistake and I apologise for it. In hindsight it was the wrong thing to do.
The resignations of two senior cabinet ministers plunge Mr Johnson into a leadership crisis weeks after he survived a no-confidence vote.
The PM won 59% of the vote, meaning he is now immune from a Conservative leadership challenge until June next year under party rules.