Khadem-Almelleh said in a statement that he had sent his letter of resignation to President Mahmoud Ahmadinejad because he could not carry on working under the current conditions.
He said that he had differences with Saffar-Harandi over how the official daily Iran should be run.
IRNA holds the publishing licence for the official daily.
This is normal in the administration of the media. You usually have differences of opinion, Khadem-Almelleh said.
A ban on the daily Iran, which had been in place for the past four months, was lifted on Tuesday.
The paper was suspended from printing after widespread anti-government demonstrations erupted in the northwest of the country in May against its publication of an insulting cartoon mocking ethnic Azeris.
Saffar-Harandi had appointed Khadem-Almelleh as head of the official news agency following Ahmadinejads election victory in June 2005.
Khadem-Almelleh was previously IRNAs bureau chief at the United Nations in New York.
The state-run news agency Fars reported that Khadem-Almelleh was replaced as IRNA chief by Jalal Sayazi, the former head of the hard-line daily Quds.
In August 2005, IRNAs then-managing director Abdollah Nasseri stepped down from his position days after he was summoned to court for questioning after Ahmadinejads campaign team filed a complaint against the agency for biased reporting against the conservative camp during the June election campaign.
He was replaced by Gholam-Hossein Eslamifar, the agencys deputy for news affairs.
