FIFA said the Swiss-Italian would, however, continue to serve on a consultancy basis until the end of the year.
The announcement came two days after De Gregorio appeared on a Swiss television chat show hosted by Roger Schawinski and told a self-deprecating joke about FIFA.
Right at the end of the programme, Schawinski asked De Gregorio to tell his favourite joke. De Gregorio said: "The FIFA president, secretary general and media director are sitting in a car. Who's driving. Answer? The police."
De Gregorio had taken over in September 2011 and had been given free reign to speak on FIFA's behalf, appearing in public debates and on television.
He faced the media alone two weeks ago on the day when seven soccer officials, wanted by United States prosecutors on corruption charges, were arrested by Swiss police in the dawn raid on the luxury hotel where FIFA accommodate visiting guests.
On that occasion, De Gregorio turned the situation on its head, saying it was part of a clean-up process FIFA themselves had initiated and that FIFA "welcomed" the police action.
He also introduced the news conference on June 2 where FIFA president Sepp Blatter announced that he would step down and call a new election.
De Gregorio was visibly upset and appeared close to tears as Blatter made his speech.
"Walter has worked incredibly hard for the past four years and we are immensely grateful for all he has done. I am glad we will be able to continue to draw on his expertise until the end of the year," said FIFA Secretary General Jerome Valcke said.
De Gregorio was head of sports at Swiss newspaper Blick, and a journalist with SonntagsZeitung and the magazine Weltwoche.
His deputy Nicolas Maingot will take over on a caretaker basis, a role he also performed before De Gregorio was appointed.
(Additional reporting by Katherine Bart; Writing by Mitch Phillips and Brian Homewood, editing by Toby Davis and Pritha Sarkar)
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