Peripheral neuropathy (PN) is a well-known adverse effect of treatment with nucleoside reverse transcriptase inhibitors (NRTIs). We performed a prospective follow-up study in HIV-infected patients on antiretroviral therapy containing NRTIs. The objective of this study was to examine the incidence of PN among patients using NRTI drugs. Data were obtained using medical records of patients continuously monitored for the efficacy and toxicity of antiretroviral therapy. The incident cases of PN were examined. Incidence rates of PN were calculated for each antiretroviral regimen that included zidovudine, zalcitabine, lamivudine, didanosine (ddI), stavudine (d4T) or didanosine+stavudine. Poisson regression was used to compare the relative risk of PN for each regimen. A total of 112 HIV-infected patients were treated with at least one NRTI-containing regimen. Thirty-two cases of PN were recorded. The lowest incidence rate (IR) of 0.13 per 100 person-years occurred in patients treated with didanosine. The highest IR for PN occurred with the didanosine+stavudine combination (IR=0.18 per 100 person-years). Compared to didanosine alone, the relative risk of PN was 1.77 (95%CI, 0.52-2.12) for stavudine, and 1.76 (95%CI, 0.95-2.49) for didanosine+stavudine. Other risk factors for PN included a low CD4 cell count and female sex. Our data show that the risk of PN is almost twice as high when stavudine is used alone or in combination with didanosine. The use of stavudine alone or in combination with didanosine should probably not be routinely recommended if other treatment options are available.