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   Formerly the Chao Ponhea Yat High School, named after a Royal ancestor of King Norodom Sihanouk, the five buildings of the complex were converted in August 1975, four months after the Khmer Rouge won the civil war, into a prison and interrogation center. The Khmer Rouge renamed the complex "Security Prison 21" (S-21) and construction began to adapt the prison to the inmates: the buildings were enclosed in electrified barbed wire, the classrooms converted into tiny prison and torture chambers, and all windows were covered with iron bars and barbed wire to prevent escapes.

   From 1975 to 1979, an estimated 17,000 people were imprisoned at Tuol Sleng (some estimates suggest a number as high as 20,000, although the real number is unknown). At any one time, the prison held between 1,000-1,500 prisoners. They were repeatedly tortured and coerced into naming family members and close associates, who were in turn arrested, tortured and killed. In the early months of S-21's existence, most of the victims were from the previous Lon Nol regime and included soldiers, government officials, as well as academics, doctors, teachers, students, factory workers, monks, engineers, etc. Later, the party leadership's paranoia turned on its own ranks and purges throughout the country saw thousands of party activists and their families brought to Tuol Sleng and murdered. Those arrested included some of the highest ranking communist politicians such as Khoy Thoun, Vorn Vet and Hu Nim. Although the official reason for their arrest was "espionage," these men may have been viewed by Khmer Rouge leader Pol Pot as potential leaders of a coup against him. Prisoners' families were often brought en masse to be interrogated and later murdered at the Choeung Ek extermination center.

  In 1979, the prison was uncovered by the invading Vietnamese army. In 1980, the prison was reopened by the government of the People's Republic of Kampuchea as a historical museum memorializing the actions of the Khmer Rouge regime.

The museum is open to the public, and receives an average of 500 visitors every day.