The indictments were handed down Thursday by the court as it moves to the second of a series of cases concerning the Khmer Rouge and the deaths of 1.7 million people from 1975 to 1979, The New York Times reported.
The quartet, in custody since 2007, have denied the charges against them. The defendants are Ieng Sary, 84, who was foreign minister; his wife, Ieng Thirith, 78, a former minister of social welfare; Khieu Samphan, 78, who was head of state; and Nuon Chea, 84, known as Brother No 2.
Khmer Rouge's leader, Pol Pot, died in 1998.
In the first case, Kaing Guek Eav, known as Duch, was sentenced to 19 years in prison for overseeing the torture and death of at least 14,000 people in the Tuol Sleng prison, the main Khmer Rouge penal facility.
Experts said the second case was more important than the Duch trial, because of the stature of the defendants and for the process of the tribunal, trying to apply international standards of justice within the Cambodian court system, The Times said.
The Cambodian government has accused the tribunal of corruption among its Cambodian employees and political interference. The government also opposed indicting additional suspects and resisted requests for testimony from six top government officials who were members of the Khmer Rouge.
The four are scheduled to appear in court in January for a procedural hearing, Substantive court sessions are scheduled to start later in 2011.