White matter disease is a relatively common neuropathological change observed in the central nervous system (CNS) tissues of patients with AIDS at autopsy. This disease ranges from small foci of myelin loss to extensive areas of demyelination. In the studies reported here, four of six unselected adult patients with AIDS had areas of demyelination in their CNS tissues at the time of their deaths. In the tissues examined, the severity of the demyelinative disease varied among the patients from a single focus of demyelination to essentially confluent loss of myelin in subcortical white matter and other CNS structures. The demyelinative disease in the brains of these patients was closely associated with active HHV-6 infection. The infected cells were present only in areas of demyelination, and they were never observed in tissue areas free of pathological changes. The HHV-6-associated neuropathology observed in the brains of these patients was identical to that described in an adult bone marrow transplant (BMT) patient with fatal HHV-6 encephalitis. Thus HHV-6-induced white matter disease appears to be a distinct pathological syndrome. Pathogenic mechanisms involved in this disease are unknown. However, the existence of HHV-6 leukoencephalopathy in a BMT patient demonstrates the potential for HHV-6 leukoencephalopathy in a BMT patient demonstrates the potential for HHV-6 to cause this syndrome without need for a cofactor or copathogen such as HIV.