Nucleoside analogue reverse transcriptase inhibitors are a critical component of antiretroviral therapy in HIV-infected persons. Several of these medications cause painful, dose-limiting peripheral neuropathy (PN), which may develop earlier and more intensely in persons with preexisting neuropathy. The prevalence of baseline peripheral neuropathy in injection drug users (IDUs), one of the largest populations of HIV-infected persons, has not been described, yet has important implications for the selection of antiretroviral therapy. The authors performed a cross-sectional study of PN in 212 HIV-seronegative and HIV-seropositive IDUs using detailed neurologic histories, physical examinations, quantitative electrophysiologic study, and quantitative sensory testing. Data were used to assign patients to one of four positive categories of PN or one of two negative categories. PN was present in 24.5% of HIV-seronegative IDUs, three to four times the reported frequency for HIV-seronegative persons in the general or male homosexual population. PN was present in 32.1% of HIV-seropositive patients. PN was axonal in nature and associated with increased age and alcohol use. PN was asymptomatic in 81% of HIV-seronegative and 71% of HIV-seropositive patients with PN. There is a high prevalence of PN in HIV-seronegative IDUs. Although these PNs do not seem to predispose HIV-seropositive IDUs to HIV-related PN, they may increase the likelihood of iatrogenic neuropathy. Intravenous drug users may need more diligent monitoring when administered nucleoside analogues than patients in risk groups with lower endemic rates of PN.