Background: Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired renal failure and affects mortality and morbidity. There has been no study comparing the efficacy of N-acetylcysteine (NAC) and ascorbic acid that have potential for CIN prevention in patients with renal insufficiency. Methods: We conducted a prospective randomized controlled trial. A total of 212 patients who had pre-existing renal impairment with basal creatinine clearance ≤60 mL/min and/or serum creatinine (SCr) level of ≥1.1 mg/dL, were randomized to have either high-dose NAC (1,200 mg orally twice a day before and on the day of coronary catheterization, n = 106) or ascorbic acid (3 g and 2 g orally before, and 2 g twice after coronary catheterization with a 12-hour interval, n = 106). The primary end point was the maximum increase of SCr level, and the secondary end point was the incidence of CIN. Results: The maximum increase of SCr level was significantly lower in NAC group than in ascorbic acid group as follows: -0.03 ± 0.18 mg/dL versus 0.04 ± 0.20 mg/mL, respectively (P = .026). Patients with diabetes or who had received a high dose of contrast media experienced significantly less rise of SCr level with NAC than ascorbic acid; in diabetic subgroup, -0.05 ± 0.22 mg/dL versus 0.09 ± 0.29 mg/mL, respectively (P = .020); in patients with high dose of dye, -0.03 ± 0.17 mg/dL versus 0.04 ± 0.21 mg/mL, respectively (P = .032). The incidence of CIN, the secondary end point, tended to be in favor of NAC rather than ascorbic acid, 1.2% versus 4.4%, respectively (P = .370). Notably, among the diabetes patients, the NAC significantly lowered CIN rate than ascorbic acid, 0% (0/38) versus 12.5% (4/32), respectively (P = .039). Conclusion: High-dose NAC seems more beneficial than ascorbic acid in preventing contrast-induced renal function deterioration in patients, especially diabetic patients, with renal insufficiency undergoing coronary angiography.