FIFA says De Gregorio "has decided to relinquish his office with immediate effect" but will stay on as consultant until the end of the year.
The Swiss former journalist joined FIFA in 2011 after working on Blatter's campaign team during that year's presidential election.
FIFA secretary general Jerome Valcke says he is glad "we will be able to continue to draw on (De Gregorio's) expertise until the end of the year."
FIFA says De Gregorio's deputy, Nicolas Maingot, will step up to the director's position.
The election to replace Blatter is expected between December and March.