Ieng Thirith, a French-educated revolutionary who was 83 when she died, was one of the few women in the leadership of the communist movement behind the horrors of the "Killing Fields" era.
She was one of just a handful of suspects charged by Cambodia's UN-backed war crimes court, but was freed in 2012 when the case against her was suspended after the court ruled she was unfit to stand trial due to progressive dementia.
The sister-in-law of late Khmer Rouge leader Pol Pot, she served as the regime's social affairs minister alongside her husband, former foreign minister Ieng Sary.
At one point this year, she had been hospitalised in Thailand with heart, bladder and lung problems.
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In the end she passed away in a former Khmer Rouge stronghold on the border with Thailand were many regime leaders settled after they were ousted by the Vietnamese.
"The accused passed away at approximately 10.30 am (0330 GMT) on 22 August in Pailin, Cambodia," the UN-backed tribunal said in a statement.
The suspension of the case against her was a bitter blow to many who survived the regime, blamed for the deaths of up to two million people. The charges against her of war crimes, genocide and crimes against humanity were never dropped, however.
The Khmer Rouge wiped out nearly a quarter of the population through starvation, forced labour and execution, in a bid to forge an agrarian utopia.
Her husband Ieng Sary died in 2013, aged 87, before a verdict was delivered in his trial.
"She was an influential party member who wielded nationwide power as the regime's minister of social affairs.