Health minister Greg Hunt has joined a number of other ministers in resigning from the Cabinet.
Mr Hunt's resignation comes as prime minister Malcolm Turnbull faces increasing pressure to resign in the face of a mass exodus from his ministry.
Mr Hunt backed former health minister Peter Dutton in the first leadership challenge earlier this week and could stand as his deputy in a second leadership ballot.
It is speculated treasurer Scott Morrison could stand for leader against Peter Dutton.
As deputy leader, Mr Hunt could choose his portfolio, including to remain in health.