Background Cystatin C level predicts mortality more strongly than serum creatinine level. It is unknown whether this advantage extends to other outcomes, such as kidney failure, or whether other novel renal filtration markers share this advantage in predicting outcomes. Study Design Observational cohort study. Setting & Participants 9,988 participants in the Atherosclerosis Risk in Communities (ARIC) Study, a population-based study in 4 US communities, followed for approximately 10 years. Predictors Serum creatinine–based estimated glomerular filtration rate calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFRCKD-EPI ) and cystatin C, β-trace protein (BTP), and β2 -microglobulin (B2M) levels. Outcomes Mortality, coronary heart disease, heart failure, and kidney failure. Results Higher cystatin C and B2M concentrations were associated more strongly with mortality (n = 1,425) than BTP level and all were associated more strongly than eGFRCKD-EPI (adjusted HR for the upper 6.7 percentile compared with the lowest quintile: 1.6 95% CI, 1.3-1.9 for eGFRCKD-EPI , 2.9 95% CI, 2.3-3.6 for cystatin C level, 1.9 95% CI, 1.5-2.4 for BTP level, and 3.0 95% CI, 2.4-3.8 for B2M level). Similar patterns were observed for coronary heart disease (n = 1,279), heart failure (n = 803), and kidney failure (n = 130). The addition of cystatin C, BTP, and B2M levels to models including eGFRCKD-EPI and all covariates, including urinary albumin-creatinine ratio, significantly improved risk prediction for all outcomes ( P < 0.001). Limitations No direct measurement of GFR. Conclusions B2M and, to a lesser extent, BTP levels share cystatin C's advantage over eGFRCKD-EPI in predicting outcomes, including kidney failure. These additional markers may be helpful in improving estimation of risk associated with decreased kidney function beyond current estimates based on eGFRCKD-EPI.