US President Barack Obama is set to confirm that Chief of Staff Rahm Emanuel will resign to run for the post of Chicago mayor.
Mr Obama has called a press conference for Friday afternoon in the White House to make a "personnel announcement".
US sources said the likely interim replacement would be Pete Rouse, who served as Mr Obama's chief of staff in the US Senate.
Mr Emanuel has made no secret of his desire to run for mayor one day.
The position of chief of staff is considered one of the most influential in the White House, and presidential aides have admitted Mr Emanuel's departure will be a loss to the administration.
The 50-year-old - who has a reputation for brashness and abrasiveness - is a native of Chicago and represented Illinois's 5th district in Congress for six years.
Pundits have tipped Mr Emanuel to replace Chicago mayor Richard M Daley, since the latter announced on 7 September that he would be stepping down.
Mr Daley has been mayor of Chicago since 1989.
Mr Emanuel has shown himself to be a strong force in the White House.
White House spokesman Robert Gibbs would not confirm Mr Emanuel's departure but said of him: "The title 'chief of staff' in many ways says it all. He has been the energetic, inspirational leader of us, taking the president's promises and agenda and enacting them into law."
Pete Rouse, 64, is a very different figure, shunning the spotlight. But analysts say he has built up strong relationships around Washington over a long period and is a good troubleshooter.
Mr Rouse, who holds degrees from the London School of Economics and Harvard's Kennedy School of Government, gained the respect of lawmakers and was even sometimes referred to as the 101st senator in the 100-seat chamber during his years serving as chief of staff to former Senate Democratic Leader Tom Daschle.
When asked about Mr Rouse, Mr Gibbs said: "Pete has been with senator-elect, senator, president-elect and now President Obama. There is a complete loyalty and trust with somebody like Pete."
However, Mr Rouse will face competition for the post when it becomes available on a permanent basis, likely to be after the 2 November congressional elections.
Deputy National Security Adviser Tom Donilon, the vice-president's aide Ron Klain, former Senate Majority Leader Tom Daschle, and ex-Clinton chief of staff John Podesta, may all be considered.
Mr Obama may wait until after the mid-term elections to permanently fill the position of chief of staff because the president is poised to face a very different political landscape in both the Senate and House of Representatives.
In recent weeks, other top officials have announced their departures, including budget director Peter Orszag and economist Lawrence Summers, who is set to leave his position as the director of the National Economic Council at the end of the year.
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