OBJECTIVE:: To evaluate the effect of HIV infection on longitudinal changes in kidney function and to identify independent predictors of kidney function changes in HIV-infected individuals. DESIGN:: A prospective cohort. METHODS:: Cystatin C was measured at baseline and at the 5-year follow-up visit of the Study of Fat Redistribution and Metabolic Change in HIV infection in 554 HIV-infected participants and 230 controls. Control participants were obtained from the Coronary Artery Risk Development in Young Adults study. Glomerular filtration rate (eGFRcys) was estimated using the formula 76.7 × cysC. RESULTS:: Compared with controls, HIV-infected participants had a greater proportion of clinical decliners (annual decrease in eGFRcys > 3 ml/min per 1.73 m; 18 versus 13%, P = 0.002) and clinical improvers (annual increase in eGFRcys > 3 ml/min per 1.73 m; 26 versus 6%, P < 0.0001). After multivariable adjustment, HIV infection was associated with higher odds of both clinical decline (odds ratio 2.2; 95% confidence interval 1.3, 3.9, P = 0.004) and clinical improvement (odds ratio 7.3; 95% confidence interval 3.9, 13.6, P ≤ 0.0001). Among HIV-infected participants, a decrease in HIV viral load during follow-up was independently associated with clinical improvement; conversely, higher baseline and an increase in viral load during follow-up were associated with clinical decline. No individual antiretroviral drug or drug class appeared to be substantially associated with clinical decline or improvement. CONCLUSION:: Compared with controls, HIV-infected persons were more likely both to have clinical decline and clinical improvement in kidney function during 5 years of follow-up. The extent of viremic control had a strong association with longitudinal changes in kidney function. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.