Central nervous system (CNS) specimens from 10 immunocompetent patients with herpes simplex encephalitis (HSE) and 3 infants with congenital cytomegalovirus (CMV) encephalitis were analyzed to determine whether apoptosis is a feature of CNS injury in these patients. Apoptotic neurons and glia were detected in significant numbers in acute HSE and CMV encephalitis. Occurring predominantly in areas of productive viral infection, apoptosis appeared to result from direct viral injury to neurons and was not dependent on inflammatory T cell responses. In contrast to patients with acute cases, patients with late sequelae of HSE or CMV had no detectable virus and minimal neuronal or glial apoptosis, regardless of the degree of inflammation. This is the first demonstration of apoptotic neuronal death in humans with HSE. These results suggest that neuronal apoptosis is an important contributing factor to acute CNS injury and may serve as a novel therapeutic target in these patients.