Lesions of the central nervous system (CNS) in 23 patients with the acquired immunodeficiency syndrome (AIDS) were compared with control cases for the presence of serum protein by immunoperoxidase staining. A sensitive immunostaining kit in conjunction with rabbit antisera to human serum, albumin, immunoglobulins and complement component 3c was used to demonstrate specific immunoreactivity in paraffin-embedded sections. Most AIDS patients with CNS lesions had serum protein immunoreactivity in some neurons, glial cells (including astrocytes), gliomesenchymal cell nodules, vascular endothelial cells, inflammatory cells or microvascular walls. Cases with the most necrosis tended to have the least immunostaining. Immunoreactivity for IgG and fixed complement in anatomically intact or morphologically altered neural cells may indicate cellular lesions and potential cellular necrosis beyond the damage indicated by routine studies alone. Part of this immunoreactivity might represent a humoral autoimmune response.