BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is associated with poor outcomes, but is challenging to predict from information available before surgery. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: The TRIBE-AKI (Translational Research Investigating Biomarker Endpoints in Acute Kidney Injury) Consortium enrolled 1,147 adults undergoing cardiac surgery at 6 hospitals from 2007-2009; participants were selected for high AKI risk. PREDICTORS: Presurgical values for cystatin C, creatinine, and creatinine-based estimated glomerular filtration rate (eGFR) were categorized into quintiles and grouped as "best" (quintiles 1-2), "intermediate" (quintiles 3-4), and "worst" (quintile 5) kidney function. OUTCOMES: The primary outcome was AKI Network (AKIN) stage 1 or higher; ≥0.3 mg/dL or 50% increase in creatinine level. MEASUREMENTS: Analyses were adjusted for characteristics used clinically for presurgical risk stratification. RESULTS: Average age was 71 ± 10 years (mean ± standard deviation); serum creatinine, 1.1 ± 0.3 mg/dL; eGFR-Cr, 74 ± 9 mL/min/1.73 m(2); and cystatin C, 0.9 ± 0.3 mg/L. 407 (36%) participants developed AKI during hospitalization. Adjusted odds ratios for intermediate and worst kidney function by cystatin C were 1.9 (95% CI, 1.4-2.7) and 4.8 (95% CI, 2.9-7.7) compared with 1.2 (95% CI, 0.9-1.7) and 1.8 (95% CI, 1.2-2.6) for creatinine and 1.0 (95% CI, 0.7-1.4) and 1.7 (95% CI, 1.1-2.3) for eGFR-Cr categories, respectively. After adjustment for clinical predictors, the C statistic to predict AKI was 0.70 without kidney markers, 0.69 with creatinine, and 0.72 with cystatin C. Cystatin C also substantially improved AKI risk classification compared with creatinine, based on a net reclassification index of 0.21 (P < 0.001). LIMITATIONS: The ability of these kidney biomarkers to predict risk of dialysis-requiring AKI or death could not be assessed reliably in our study because of a small number of patients with either outcome. CONCLUSIONS: Presurgical cystatin C is better than creatinine or creatinine-based eGFR at forecasting the risk of AKI after cardiac surgery.