Context A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied. Objective To evaluate whether combining creatinine, cystatin C, and urine albuminto- creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone. Design, Setting,andParticipants Prospective cohort study involving26 643USadults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m2 and ACR of either <30 or ≥30 mg/g. Main Outcome Measures All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years. Results Participants had amean age of 65 years,40%were black, and54%werewomen. Of26 643 participants, 1940 died and 177 developed end-stage renal disease.Among participants withoutCKDdefined by creatinine,24%did not haveCKDby either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0- 5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2-4.7) for those withCKDdefined by creatinine and cystatin C, and 5.6 (95% CI, 3.9-8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) hadCKDdetected byACRor cystatin C. Compared with participants whodid not haveCKDby any measure, the HRs for mortality were 1.7 (95% CI, 1.4-1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9-2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4-3.7) for participants with CKDdefined by both measures. Risk of incident end-stage renal diseasewashigheramong those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7-40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05-2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate wasamongpersons missed by the creatinine measure but detected by bothACRand cystatinC(rate per 1000 personyears, 6.4; 95% CI, 3.6-11.3). Net reclassification improvement for death was 13.3% (P<.001) and for end-stage renal disease was 6.4% (P<.001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR. Conclusion Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease. © 2011 American Medical Association.