Vacuolar myelopathy (VM) is a frequent neurological complication of the acquired immune deficiency syndrome (AIDS). A suspected connection between VM and human immunodeficiency virus (HIV) has been based only on HIV isolation from affected spinal cord tissue. We report here an AIDS patient dying after 14 months of progressive dementia, including 3 months of spinal signs and symptoms. At autopsy, the brain revealed moderate diffuse damage of the white matter compatible with HIV-induced progressive diffuse leukoencephalopathy. The spinal cord showed VM mainly in the lateral and the posterior columns. Mono- and multinucleated macrophages were localized within intramyelinic and periaxonal vacuoles. Light and electron microscopic immunocytochemistry revealed the presence of HIV antigens restricted to mono- and multinucleated macrophages within the spongy lesions. Productive HIV infection is documented for the first time within VM lesions of this case. Therefore, VM should be included among HIV-induced lesions of the central nervous system. The intimate relation of infected macrophages to vacuolar myelinopathy could suggest secretion of a myelinotoxic factor by macrophages productively infected by HIV. Immune electron microscopy appears as promising tool to detect HIV in tissue even when the density of virus may be low.