The aim of this study is to assess the efficacy of high-dose atorvastatin on the prevention of contrast-induced nephropathy (CIN) in patients with acute coronary syndrome (ACS) undergoing percutaneous intervention and observe the incidence of cystatin C (CyC)-based CIN. A total of 496 patients with ACS were randomly assigned to either the control group (247 patients receiving conventional dose atorvastatin 10 mg daily from 1 day before to 3 days after contrast administration) or the high-dose atorvastatin group (249 patients receiving atorvastatin 40 mg daily for the same perioperative period). The baseline characteristics of the 2 groups were similar. The primary end point of serum creatinine (SCr)-based CIN occurred in 31 patients in the control group and 16 patients in the high-dose atorvastatin group (12.6% vs 6.4%; P = .02). Cystatin C–based CIN developed in 90 patients in the control group and 46 patients in the high-dose atorvastatin group (36.4% vs 18.5%; P < .001). A multivariable analysis revealed that high-dose atorvastatin was independently associated with a decreased risk of CIN. Our study demonstrated that prophylactic treatment with high-dose atorvastatin reduced the risk of both SCr and CyC-based CIN and suggested that CyC was a more reliable marker for early diagnosis of CIN compared with SCr.