A family of three white-faced saki monkeys (Pithecia pithecia pithecia) died 48-96 hours after the onset of anorexia, nasal discharge, pyrexia and oral ulceration. One animal also had clonic seizures. Lesions found post-mortem consisted of oral and esophageal ulcers, hepatic and intestinal necrosis, meningoencephalitis and sporadic neuronal necrosis. Intranuclear inclusion bodies and syncytial cells were present in oral lesions and affected areas of liver. Herpes simplex virus 1 (HSV-1) was identified as the etiology of disease by virus isolation, polymerase chain reaction, or in situ hybridization in all three animals. Immunohistochemistry for detection of apoptotic DNA and activated caspase-3 showed significant levels of apoptosis in oral and liver lesions and occasional apoptotic neurons in the brain. These findings demonstrate the vulnerability of white-faced saki monkeys to HSV-1 and provide initial insight into the pathogenesis of fatal HSV-1-induced disease, indicating that apoptosis plays a significant role in cell death.