The histopathological and immunopathological features of peripheral neuropathy were investigated in 2 1 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). Clinical syndromes observed in the 11 (52%) symptomatic patients included distal symmetrical polyneuropathy (DSPN) and chronic inflammatory demyelinative polyneuropathy (CIDP). Specimens from 19 of 20 patients (95%), both symptomatic and asymptomatic, had histopathological evidence of moderate or severe demyelination (79%), axond degeneration (36%), and mononuclear cell inflammation (37%). Nerves from patients with CIDP and DSPN showed similar degrees of demyelination and axonal degeneration, but inflammation was more intense in CIDP. Immunohistochemical staining identified the majority of inflammatory cells as T lymphocytes or macrophages, with a predominance of CD8+ cytotoxic/suppressor cells. Diffuse immunostaining for human leukocyte antigen (HLA)-DR was present on endothelial cells, mononuclear inflammatory cells, and Schwann cells, and variable patchy immunostaining for HLA-DR was present on nerve fibers. Control nerve specimens showed staining for HLA-DR limited to endothelial, and a few mononuclear, cells. The patterns of immunostaining were similar for AIDS and ARC patients. Human immunodeficiency virus (HIV) was cultured from peripheral nerve in 3 patients, but HIV antigen was not detected by immunohistochemical staining of 8 specimens. The findings implicate HIV infection in nerve, with T cell-and macrophage-mediated tissue destruction as the pathogenetic mechanism of the AIDS/ARC neuropathy.