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.
Mr Emanuel - 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 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".
BBC News
