Background: Compared with controls, human immunodeficiency virus (HIV)-infected persons have a greater prevalence of kidney disease, assessed according to high cystatin C level and albuminuria, but not according to creatinine level. However, the clinical importance of increased cystatin C level and albuminuria in the HIV-infected population has not been studied. Study Design: We conducted an observational cohort study to determine the association of kidney disease (measured according to albuminuria, cystatin C, and serum creatinine) with mortality. Setting & Participants: 922 HIV-infected persons enrolled in the FRAM (Fat Redistribution and Metabolic Change in HIV Infection) Study. Predictor: Serum cystatin C and serum creatinine levels were used to estimate glomerular filtration rates (eGFRSCysC and eGFR SCr, respectively). Albuminuria was defined as a positive urine dipstick result (<1+) or urine albumin-creatinine ratio >30 mg/g. Outcome: 5-Year mortality. Results: At baseline, decreased kidney function (eGFR SCysC <60 mL/min/1.73 m2) or albuminuria was present in 28% of participants. After 5 years of follow-up, mortality was 48% in those with both eGFRSCysC <60 mL/min/1.73 m2 and albuminuria, 23% in those with eGFRSCysC <60 mL/min/1.73 m2 alone, 20% in those with albuminuria alone, and 9% in those with neither condition. After multivariable adjustment for demographics, cardiovascular risk factors, HIV-related factors, and inflammatory marker levels, eGFRSCysC <60 mL/min/1.73 m2 and albuminuria were associated with a nearly 2-fold increase in mortality, whereas eGFRSCr <60 mL/min/1.73m 2 did not appear to have a substantial association with mortality. Together, eGFRSCysC <60 mL/min/1.73 m2 and albuminuria accounted for 17% of the population-level attributable risk of mortality. Limitations: Vital status was unknown in 261 participants from the original cohort. Conclusions: Kidney disease marked by albuminuria or increased cystatin C level appears to be an important risk factor for mortality in HIV-infected individuals. A substantial proportion of this risk may be unrecognized because of the current reliance on serum creatinine to estimate kidney function in clinical practice. © 2010 National Kidney Foundation, Inc.