To better evaluate the renal safety profile of tenofovir, we performed a retrospective study of HIV-infected antiretroviral-naïve patients starting a first antiretroviral therapy between July 2004 and July 2008, and followed-up for 24 months. The glomerular filtration rate (GFR) was calculated using the MDRD formula, and tubular dysfunction was diagnosed with 2 or more of the following: proteinuria, glucosuria, hypouricemia, hypophosphatemia and hypokalemia. Overall, 324 patients were enrolled: 201 were tenofovir-exposed and were compared with 123 tenofovir-unexposed subjects. In both the unadjusted and adjusted analyses, tenofovir-exposed subjects had a significantly greater decline in GFR and a significantly higher incidence of proximal tubular dysfunction through 24 months. Reduced glomerular and tubular functions were significantly associated with older age, diabetes, hypertension and concomitant therapy with a protease inhibitor.