In comments published on Sunday by the Swiss magazine Blick, Del Ponte expressed frustration about the commission and criticised President Bashar al-Assad's regime, the Syrian opposition, and the international community's inaction.
"We have had absolutely no success," she told Blick on the sidelines of the Locarno film festival on Sunday. "For five years we've been running up against walls."
Del Ponte, who gained fame as the prosecutor for the international war crimes tribunals that investigated atrocities in Rwanda and Yugoslavia.
She has repeatedly decried the Security Council's refusal to appoint a similar court for Syria's six-and-a-half-year civil war.
Permanent UNSC member Russia, which can veto council actions, is a key backer of Assad's government. Moscow has repeatedly blocked strong international action against Damascus.
"I give up. The states in the Security Council don't want justice," Del Ponte said, adding that she planned to take part in the last meeting in September.
"I can't any longer be part of this commission which simply doesn't do anything."
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Appointed in September 2012, Del Ponte was quoted by Blick as saying she now thinks she was put into the role "as an alibi".
"I've written my letter of resignation already and will post it in the coming days," she said.
She did not immediately respond to a text message from The Associated Press seeking comment.
In her comments to Blick, Del Ponte described Syria as a land without a future.
"Believe me, the terrible crimes committed in Syria I neither saw in Rwanda nor ex-Yugoslavia," she said. "We thought the international community had learned from Rwanda. But no, it learned nothing."
At first in Syria, "the opposition (members) were the good ones; the government were the bad ones", she was quoted as saying.
But after six years, Del Ponte concluded: "In Syria, everyone is bad. The Assad government is committing terrible crimes against humanity and using chemical weapons. And the opposition, that is made up only of extremists and terrorists anymore."
| The commission issued a statement saying it was aware since mid-June of Del Ponte’s plans to leave and insisted that its work “must continue” to help bring perpetrators in Syria to justice. |
End of Syria war-crime inquiry?
The commission issued a statement saying it was aware since mid-June of Del Ponte's plans to leave and insisted that its work "must continue" to help bring perpetrators in Syria to justice.
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Del Ponte's resignation shrinks the commission to two members after Thai professor and former human rights investigator Vitit Muntarbhorn left last year to become the first-ever UN's independent expert investigating violence and discrimination based on sexual orientation.
The commission was set up in August 2011 by the Human Rights Council to investigate crimes in Syria, no matter who committed them.
Since then, it has compiled thousands of interviews and keeps a list of suspected war criminals under lock and key at the offices of the UN High Commissioner for Human Rights in Geneva.
But Del Ponte said that as long as the Security Council didn't put in place a special tribunal for war crimes in Syria, all commission reports were pointless.
The issue of accountability for war crimes in Syria has largely taken a back seat to diplomatic efforts to end the war in recent months.
The commission's relevance has also come into question after the UN General Assembly - acting in the face of the Security Council inaction - voted in December to set up an investigative body to help document and prepare legal cases to possibly prosecute the most serious violations in Syria's war that is estimated to have left at least 400,000 dead.
The Syrian conflict began when the Baath regime, in power since 1963 and led by Bashar al-Assad.
It responded with military force to peaceful protests demanding democratic reforms during the Arab Spring wave of uprisings, triggering an armed rebellion fuelled by mass defections from the Syrian army.
According to independent monitors, hundreds of thousands of civilians have been killed in the war, mostly by the regime and its powerful allies. Millions more have been displaced both inside and outside of Syria.
The brutal tactics pursued mainly by the regime - which have included the use of chemical weapons, sieges, mass executions and torture against civilians - have led to war crimes investigations.