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We sought to identify factors associated with the clinical diagnosis of symmetrical peripheral neuropathy (SPN) during the era of highly active antiretroviral therapy (HAART) in a retrospective, longitudinal cohort analysis.Patients infected with human immunodeficiency virus type 1 were evaluated for clinical signs of SPN and its association with immunologic, virologic, clinical, and drug treatment factors by means of univariate and multivariate logistic regression analyses.Of 2515 patients, 329 (13.1%) received a diagnosis of SPN. In the logistic regression analysis, statistically significant non—drug-based risk factors for SPN were age >40 years (adjusted odds ratio [aOR], 1.17), diabetes mellitus (aOR, 1.79), white race (aOR, 1.33), nadir CD4+ T lymphocyte count <50 cells/mm3 (aOR, 1.64), CD4+ T lymphocyte count 50-199 cells/mm3 (aOR, 1.40), and viral load >10,000 copies/mL at first measurement (aOR, 1.44). Although initial use of didanosine, stavudine (40 mg b.i.d.), nevirapine, or 4 protease inhibitors was associated with SPN (ORs for all 4 treatments, >1.41), the strength of association decreased with continued use of all medications studied.Since HAART was introduced, the incidence of SPN has decreased. Host factors and signs of increased disease severity were associated with an increased risk of developing SPN during the initial period of exposure to drug therapy. Immunity improved and the risk of SPN decreased with continued use of HAART. Delaying the initiation of therapy may select those individuals who will be more likely to develop SPN, and earlier initiation of HAART may decrease the risk of developing this common problem, as well as increase the therapeutic effects and decrease the toxic effects of the drugs.