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To better characterize the long-term effects of tenofovir on renal function in a large managed care organization.We performed a retrospective cohort analysis in Kaiser Permanente for years 2002 to 2005 comparing renal function among antiretroviral naïve patients initiating a tenofovir-containing regimen (964 patients) or tenofovir-sparing regimens (683 patients). We evaluated glomerular filtration rate (GFR, [Modification of Diet in Renal Disease equation]), serum creatinine, and the development of renal proximal tubular dysfunction. We report multivariable hazard ratios (HR, Cox modeling) and linear outcomes (repeated measures) with predictors retained if P < 0.10 (backward selection). Potential predictor variables included in multivariate models were age, sex, Black race, baseline laboratories (including CD4 count), history of diabetes mellitus, hypertension, malignancy, hepatitis, and concurrent medications.Overall, tenofovir-exposed patients had a larger relative decline in GFR through 104 weeks (−7.6 mL/min/1.73 m2 relative to tenofovir-sparing, P < 0.001); the degree of the difference varied by baseline GFR, with the greatest effect seen in those patients with GFR greater than 80 mL/min/1.73 m2. Tenofovir-exposed patients had greater development of proximal tubular dysfunction over time (at 52 wk: HRadjusted = 1.95 [P = 0.01] and at 104 wk: HRadjusted = 5.23 [P = 0.0004]) and had greater risk of medication discontinuation (HRadjusted = 1.21, P = 0.02), especially as renal function worsened. Viral control and CD4 count changes were similar between the two groups.Tenofovir is associated with greater effect on decline in renal function and a higher risk of proximal tubular dysfunction in antiretroviral naïve patients initiating antiretroviral therapy.