JOIN USThe case, described as the most complex since the landmark Nazi trials after World War II, has been long awaited by survivors of the regime, which wiped out nearly a quarter of the population.
The elderly defendants, including "Brother Number Two" Nuon Chea and former head of state Khieu Samphan, looked frail as they sat in the dock.
"The (court) opens the initial hearing of case 002," chief judge Nil Nonn told the court.
In its first trial, the tribunal sentenced former prison chief Kaing Guek Eav -- also known as Duch -- to 30 years in jail last July for overseeing the deaths of 15,000 people.
The four accused face charges including genocide, crimes against humanity and war crimes over the deaths of up to two million people from starvation, overwork, torture or execution during the Khmer Rouge's brutal 1975-79 rule.
The genocide charges relate specifically to the murders of Vietnamese people and ethnic Cham Muslims.
They deny the accusations and the trial, which has been long awaited by victims in the traumatised nation, is expected to be long and complex.
"I am not happy with this hearing," Nuon Chea said in a brief and unexpected statement, wearing his trademark sunglasses. He added that his lawyer would explain why later.
The trial is seen as vital to healing the traumatised nation's deep scars.
"This trial is very important to find justice for those who died and for the survivors," said Cambodian farmer Khem Nareth, 56, who lost his mother and brother under the regime.
"I want the court to jail the four leaders for life. The regime was very cruel," he added.
The initial hearing is scheduled to last four days and will focus on expert and witness lists and preliminary legal objections.