OBJECTIVE: : Acute kidney injury is a frequent and serious complication of cardiopulmonary bypass. In current clinical practice, serum creatinine is used to detect acute kidney injury. Cystatin C is a novel biomarker for kidney function that has been shown to be superior to serum creatinine in predicting acute kidney injury in adults after cardiopulmonary bypass. The aim of this study was to determine whether early cystatin C levels predict acute kidney injury associated with cardiopulmonary bypass in pediatric patients undergoing cardiac surgery and if cystatin C could predict pediatric-modified RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) class and renal injury as determined by estimated glomerular filtration rate. We also investigated whether ultrafiltration during cardiopulmonary bypass affects cystatin C levels. DESIGN: : Prospective, observational cohort study. SETTING: : Cardiac intensive care unit in a tertiary, academic pediatric hospital. PATIENTS: : One hundred pediatric patients who underwent cardiac surgery involving cardiopulmonary bypass. INTERVENTIONS: : None. MEASUREMENTS AND MAIN RESULTS: : Acute kidney injury was defined as a 50% increase in serum creatinine from a preoperative baseline anytime through postoperative day 4. Severity of acute kidney injury was determined by pediatric RIFLE class using estimated glomerular filtration rate criteria only. Renal injury was also determined by an absolute estimated glomerular filtration rate <80 mL/min/1.73 m. Cystatin C levels were measured before and after ultrafiltration. Twenty-eight patients (28%) developed acute kidney injury. Cystatin C predicted acute kidney injury as early as 8 hrs after surgery. When applying pediatric RIFLE criteria to the entire study, 30 patients reached "risk" and five developed "injury." Cystatin C was a good predictor of the development of "injury" (under the receiver operating characteristic curve, 0.834-0.875) and of renal injury by estimated glomerular filtration rate (under the receiver operating characteristic curve, 0.717-0.835) (all p < .05). Cystatin C levels decreased perioperatively and correlated with volume of fluid removed by ultrafiltration. CONCLUSIONS: : Cystatin C is an early predictor of acute kidney injury in children after cardiopulmonary bypass. Cystatin C is a good predictor of pediatric RIFLE classification and of decreased estimated glomerular filtration rate after cardiopulmonary bypass. Serum cystatin C may be cleared by ultrafiltration.