Dan Bartlett, counsellor to President George W Bush and one of his longest-serving aides, has resigned.
Dan Bartlett has been at Mr Bush's side since his Texas days
Mr Bartlett, who has been with Mr Bush for the past 13 years, said he was leaving to work in the private sector and spend more time with his family.
It is the first big shift in Mr Bush's inner circle since Defence Secretary Donald Rumsfeld left last November.
Mr Bush said he would miss Mr Bartlett very much, saying his contribution had been "immeasurable".
Mr Bartlett, who announced his resignation on his 36th birthday, said he had decided now was the time to concentrate on helping to raise his three children, all under four.
He has served Mr Bush since his first campaign as governor of Texas, staying by his side through six years in the White House shaped by the 9/11 terror attacks and the war in Iraq.
"It's been a hell of ride," Mr Bartlett told news agency Reuters in an interview, saying he would leave the job on 4 July.
"I figured after 13 years and a lot of experience under my belt, this was a time to turn a new chapter in my life."
Mr Bartlett has been known as someone who has the president's ear and can talk to him candidly, White House chief of staff Joshua Bolten said.
In a statement, Mr Bush said: "I value his judgment and I treasure his friendship.
"Since coming to work for me 14 years ago as I prepared to run for Governor, Dan has become a husband and a father. I understand his decision to make his young family his first priority."