Background— Cystatin C (CyC) is more sensitive than serum creatinine (sCr) to rapidly detect acute changes in renal function. Methods and Results— We measured CyC together with sCr in 410 consecutive patients with chronic kidney disease undergoing either coronary and/or peripheral angiography and/or angioplasty. sCr was assessed at baseline and 24 and 48 hours after contrast media exposure. CyC was assessed at baseline and at 24 hours. Major adverse events (including death of any cause and dialysis) at 12 months were assessed. At 48 hours after contrast media exposure, contrast-induced acute kidney injury (defined as a sCr increase ≥0.3 mg/dL) occurred in 34 patients (8.2%). A CyC increase concentration ≥10% at 24 hours after contrast media exposure was detected in 87 patients (21.2%). This was the best CyC cutoff for the early identification of patients at risk for contrast-induced acute kidney injury (negative predictive value=100%; positive predictive value=39.1%). According to the defined cutoffs (that is, increase in CyC ≥10% and sCr ≥0.3 mg/dL), major adverse events occurred in 16 of 297 patients (5.4%) without any cutoffs satisfied (group 1), in 9 of 49 patients (18.4%) with only a CyC increase ≥10% (group 2), and in 9 of 31 patients (29%) with both cutoffs satisfied (group 3). By logistic regression analysis, the independent predictors of major adverse events at 1 year were group 2 (odds ratio=2.52; 95% confidence interval, 1.17 to 5.41; P =0.02), group 3 (odds ratio=4.45; 95% confidence interval, 1.72 to 11.54; P =0.002), and baseline glomerular filtration rate (odds ratio=0.91; 95% confidence interval, 0.88 to 0.95; P <0.001). Conclusions— In patients with chronic kidney disease, CyC seems to be a reliable marker for the early diagnosis and prognosis of contrast-induced acute kidney injury.