The etiopathogenesis of peripheral neuropathy (PN) that frequently affects human immunodeficiency virus (HIV) type 1-positive patients remains undefined. Forty-seven HIV-1-positive patients with PN (8 with inflammatory demyelinating polyneuropathy and 39 with predominantly sensory polyneuropathy [PSP]) and 266 controls with symptomatic HIV-1 infection without PN were screened for antibodies to human T cell lymphotropic virus (HTLV) types I and II. The prevalence of antibodies to HTLV-II was significantly higher in patients with PSP than in controls (30.8% vs. 8.3%; P < .001). All seropositive patients with PN had HTLV-II DNA in their peripheral blood mononuclear cells by polymerase chain reaction (PCR) analysis. PCR analysis of tissues from 1 patient with PSP who died during the study showed HTLV-II proviral sequences in the femoral nerve and basal nuclei. These results support the hypothesis that HTLV-II represents an etiologic factor in the pathogenesis of a considerable proportion of PSP in patients infected with HIV-1.