OBJECTIVE: To examine long-term effects of antiretroviral therapy (ART) on kidney function, we evaluated the incidence and risk factors for chronic kidney disease (CKD) among ART-naive, HIV-infected adults and compared changes in estimated glomerular filtration rates (eGFR) before and after starting ART. METHODS: Multicenter observational cohort study of patients with at least one serum creatinine measurement before and after initiating ART. Cox proportional hazard models, and marginal structure models examined CKD risk factors; mixed-effects linear models examined eGFR slopes. RESULTS: Three thousand, three hundred and twenty-nine patients met entry criteria, contributing 10099 person-years of observation on ART. ART was associated with a significantly slower rate of eGFR decline (from -2.18 to -1.37ml/min per 1.73m per year; P=0.02). The incidence of CKD defined by eGFR thresholds of 60, 45 and 30ml/min per 1.73m was 10.5, 3.4 and 1.6 per 1000 person-years, respectively. In adjusted analyses black race, hepatitis C coinfection, lower time-varying CD4 cell count and higher time-varying viral load on ART were associated with higher CKD risk, and the magnitude of these risks increased with more severe CKD. Tenofovir and a ritonavir-boosted protease inhibitor (rPI) was also associated with higher CKD risk [hazard odds ratio for an eGFR threshold <60ml/min per 1.73m: 3.35 (95% confidence interval (CI)=1.40-8.02)], which developed in 5.7% of patients after 4 years of exposure to this regimen-type. CONCLUSION: ART was associated with reduced CKD risk in association with CD4 cell restoration and plasma viral load suppression, despite an increased CKD risk that was associated with initial regimens that included tenofovir and rPI. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.