Afghan Interior Minister Ali Ahmad Jalali has said he will resign.
Mr Jalali is said to have been at odds with President Karzai
Correspondents say Mr Jalali has been outspoken over the role of senior officials in the drugs trade.
They say he has also been at odds with President Karzai's choice of provincial officials. It is not yet known if Mr Karzai will accept the resignation.
The Interior Ministry denied any rift. A Karzai spokesman said was resigning for "personal reasons". Mr Jalali says he wants to pursue his academic career.
Correspondents say Mr Jalali is one of the most respected members of the Karzai cabinet and his departure will be seen as a setback for efforts to form a technocratic government in Afghanistan after years of war.
His going would also relieve the cabinet of one of its most powerful voices against warlords and those involved in the drugs trade.
Mr Jalali returned to Afghanistan in 2002 after years in exile in the United States.
He has openly complained that senior government officials are involved in the drugs trade, but says he is stepping down for other reasons.
"I will not work as interior minister any more. Maybe there are reasons for this and maybe not but one of the main reasons is that I wish to resume my academic research," he told the private Tolo TV station.
"I was involved in academia in the past and I feel really comfortable in that field.
"As interior minister, I tried to serve the people, too, but I think it is again time for me to resume my academic research."
A senior government official told the BBC that Mr Jalali had formally tendered his resignation to the president.
Khaleeq Ahmad, a spokesman for the president, said he had been an "excellent minister".
"We are sad he's going to leave us. It's a purely personal decision. He's going to pursue an academic career," Mr Ahmad told Associated Press.
An Interior Ministry statement later in the day said: "Ali Ahmad Jalali dismisses rumours [of a rift with the president] as baseless and strongly denies them.
"He has recently asked the president to relieve him of his reponsibilities as interior minister and give him time so Mr Jalali can continue his academic activities."
Mr Jalali served as a police officer before moving to the US after Soviet troops invaded Afghanistan in 1979.
He later worked as a journalist and writer, eventually heading Voice of America's Persian and Pashto services.