Ta Mok, one of the main leaders of Cambodia's brutal Khmer Rouge regime, has died in the capital Phnom Penh.
Nicknamed "The Butcher", he was the regime's military commander and linked to many atrocities of the 1970s.
About 1.7 million people died under the Khmer Rouge, through a combination of starvation, disease and execution.
Ta Mok was expected to be one of the first people tried for genocide and crimes against humanity at UN-backed hearings due to start next year.
He was one of only two surviving Khmer Rouge commanders in detention, and with most of the remaining figures from the regime in poor health, some analysts question whether the trials have been left too late to see justice served.
"Ta Mok passed away this morning," military doctor Tuoth Nara told reporters. "He was an old man and died of natural causes, given his poor health and respiratory problems."
Ta Mok, who was in his 80s, had been unwell since last month, suffering from high blood pressure and tuberculosis, and slipped into a coma last week.
"We are saddened by his death," said his nephew, 33-year-old Morm Mol, as he announced the news to reporters outside the Phnom Penh hospital.
Of all the Khmer Rouge leaders, Ta Mok was regarded by many as the most brutal, the BBC's Guy Delauney reports from Phnom Penh.
He played a key role in a series of massacres and purges, which started even before the Khmer Rouge took power.
Ta Mok was in charge of the forces which destroyed the former royal capital Oudong in 1974, expelling civilians and killing officials and government soldiers.
Later he instigated purges as the Khmer Rouge went to war with itself.
He eventually became the overall leader of the organisation in 1997, but he was captured two years later and spent the rest of his life in jail.
Ta Mok's death leaves a Khmer Rouge prison boss, Kaing Khek Iev, more commonly known as Duch, as the group's only surviving leader in detention.
Pol Pot died in his jungle hide-out in April 1998 from an apparent heart attack.
Many Cambodians fear they will never get a chance to see justice, because ageing Khmer Rouge defendants are dying before they face trial.
Earlier this month, judges and prosecutors from both Cambodia and other nations were sworn in for the UN-backed tribunal, which is due to start in 2007.
A spokesman for the tribunal, Reach Sambath, said on Friday that a "key resource of information" had passed away.
When he heard of Ta Mok's death, Youk Chhang, the director of the Documentation Center of Cambodia, an independent group researching the atrocities committed by the Khmer Rouge, said: "It's sad news - it's outrageous."
"Some people may be happy with this, but not the victims who have been waiting for justice for a long time," he told the Associated Press.