Ieng Sary's death will dismay victims of the regime who fear those most responsible for their suffering will escape justice. An estimated 1.7 million people died during the ultra-maoist "killing fields" revolution of the Khmer Rouge and its leader, Pol Pot.
A UN-backed tribunal was set up in Cambodia to try those responsible, but so far only one relatively low-level prison chief has been found guilty and jailed. The court's work has been hampered by funding problems and alleged interference by the Cambodian government.
Ieng Sary was one of three top Khmer Rouge leaders on trial in the court's second case. The court announced his death at 87 in a statement, saying he had been in hospital since 4 March.
"For the victims, this death narrows the scope of the trial and limits their search for truth and justice," said Elisabeth Simonneau Fort, a lawyer who represents Khmer Rouge victims at the court. "We can say that by death, Ieng Sary escapes justice."
The two remaining defendants are ex-propagandist Nuon Chea and ex-president Khieu Samphan. Many fear that only Khieu Samphan will live to hear his verdict as Nuon Chea has been in and out of hospital for years.
The case against a fourth defendant, Ieng Thirith, the wife of Ieng Sary, social affairs minister for the Khmer Rouge, was suspended last year when she was declared mentally unfit to stand trial.
Ieng Sary studied in Paris with Pol Pot and held senior positions, including that of deputy prime minister in charge of foreign affairs, between 1975 and 1979 until Vietnam invaded Cambodia, toppled the Khmer Rouge and sentenced both men to death in absentia.
They fled with Khmer Rouge loyalists to remote jungle strongholds in western Cambodia. But Ieng Sary's 1996 defection to the government, along with thousands of fighters, dealt a death blow to the movement. Pol Pot died two years later.
Though pardoned by former King Norodom Sihanouk, Ieng Sary was arrested in 2007 by the joint Cambodian-UN tribunal, the Extraordinary Chambers in the Court of Cambodia, and subsequently put on trial for genocide, crimes against humanity and breaches of the Geneva Convention.
The court, dogged from the outset by allegations of corruption, political interference and wastefulness, had spent $175 million (117 million pounds) by the end of last year and handed down just one conviction to former prison chief Kaing Guek Eav, alias "Duch", jailed for life for the deaths of more than 14,000 people.
Ieng Sary's death is "a tremendous loss for Cambodia's understanding of its own history", said Anne Heindel, legal adviser at the Documentation Center of Cambodia.
"With only two surviving senior leaders left on trial it is absolutely essential that the court be ensured sufficient funding to complete its work . . . before more ageing suspects and survivors pass away."