BACKGROUND: Contrast-induced nephropathy (CIN) is a serious condition in patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention. We compared the risk of acute CIN and the influence of preventive strategies in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. METHODS AND RESULTS: A total of 720 patients were randomized in the Prevention of Contrast-induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention (CINSTEMI) trial. Patients were randomly assigned in a 1:1:1:1 ratio to receive hydration with sodium chloride together with 1 of 4 prophylactic regimes (1) N-acetylcysteine (NAC), (2) sodium bicarbonate (NaHCO3) infusion, (3) NAC in combination with NaHCO3, or (4) hydration with sodium chloride infusion alone. Patients in cardiogenic shock were excluded. Acute CIN was defined as an increase in serum creatinine concentration >25% from the baseline value within a 3-day period. Overall, CIN occurred in 141 (21.9%) patients. The prevention treatment with NAC, NaHCO3, or the combined NAC and NaHCO3 did not reduce the rate of CIN significantly compared with hydration with intravenous sodium chloride infusion alone (20.1% versus 20.1% versus 20.8% versus 26.5%; P=NS). However, an increase in serum creatinine >25% from the baseline value to 30 day was significantly lower in patients treated with combined NAC and NaHCO3 (18.7% versus 19.1% versus 9.2% versus 21.3%; P=0.033). CONCLUSIONS: Treatment with NAC or NaHCO3 did not reduce the rate of acute CIN significantly. Combined treatment with NAC and NaHCO3 may reduce the risk of renal dysfunction after 30 days. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01160627.