US Defence Secretary Jim Mattis, a retired Marine Corps general who was known as a stabilising force in US President Donald Trump's Cabinet, will leave his job at the end of February, Trump said in a tweet.
The departure of Mattis had been anticipated since Mr Trump announced that he was withdrawing US troops from Syria despite opposition from US allies and Mr Trump's own top military officials.
In his resignation letter, Mr Mattis said he's stepping down so President Trump can have a Defence Secretary with views more aligned to his.
He added that his core belief is that the United States needs to maintain strong alliances and show respect, while it must be 'unambiguous' with countries like Russia and China.
General Jim Mattis will be retiring, with distinction, at the end of February, after having served my Administration as Secretary of Defense for the past two years. During Jim’s tenure, tremendous progress has been made, especially with respect to the purchase of new fighting....— Donald J. Trump (@realDonaldTrump) December 20, 2018
Mr Trump said he would nominate a successor to Mr Mattis shortly.
Mr Mattis joins a long list of former Trump administration senior figures who have either quit or been removed, some unceremoniously like Secretary of State Rex Tillerson who Mr Trump fired via Twitter in March.
Mr Trump's White House has had the highest turnover of senior-level staff of the past five presidents, according to the Brookings Institution think tank.