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Whereas tenofovir (TDF) exposure has been associated with decreased bone density, it remains unclear whether it is associated with increased risk of osteoporotic fractures.Patients with any osteoporotic fracture (defined as wrist, vertebral or hip fracture) occurring after HIV diagnosis were identified by International Classification of Diseases – 9th Revision (ICD-9) code in the Veterans Affairs’ Clinical Case Registry from 1988 to 2009. Osteoporotic fracture risk associated with cumulative exposure to TDF and other antiretrovirals was examined in univariate analysis and multivariate model 1 (MV1 – controlling for race, age, tobacco use, diabetes, body mass index, and hepatitis C status) and model 2 (MV2 – controlling for MV1 variables + concomitant antiretroviral exposures).Among 56 660 patients evaluated, TDF exposure (total 46 062 person-years) was associated with an osteoporotic fracture hazard ratio of 1.080 [95% confidence interval (CI) 1.02–1.15, P < 0.001] in univariate analysis, 1.06 (0.99–1.12) in MV1 and 1.06 (0.99–1.14) in MV2. Among patients entering the cohort in the highly active antiretroviral therapy (HAART) era (n = 32 439), TDF exposure was associated with a yearly hazard ratio for osteoporotic fracture of 1.16 (95% CI 1.08–1.24, P < 0.001) in univariate model, 1.13 (1.05–1.21, P = 0.001) in MV1 and 1.12 (1.03–1.21, P = 0.011) in MV2. Boosted protease inhibitor exposure was associated with hazard ratio of 1.11 (1.05–1.18, P = 0.001) in univariate model, 1.08 (1.01–1.15, P = 0.026) in MV1 and 1.05 (0.97–1.13, P = 0.237) in MV2. Among protease inhibitors, lopinavir/ritonavir (LPV/RTV) had an osteoporotic fracture hazard ratio of 1.09 (CI 1.00–1.20, P = 0.051) in MV2.Cumulative exposure to TDF and, among protease inhibitors, LPV/RTV was independently predictive of increased risk of osteoporotic fracture in the HAART era.