The renoprotective effect of N-acetylcystein in patients undergoing coronary artery bypass graft surgery is controversial. We assessed the renoprotective effect of the highest dose of N-acetylcystein sanctioned for clinical use in a prospective, double-blind, placebo-controlled study including 70 chronic kidney disease patients, stage 3 or 4, who underwent coronary artery bypass graft surgery, on cardiopulmonary bypass (CPB) and off CPB, and were randomly allocated to receive either N-acetylcystein 150 mg/kg followed by 50 mg/kg for 6 hours in 0.9% saline or only 0.9% saline. Acute kidney injury was defined by the Acute Kidney Injury Network classification. The incidence of kidney injury was reduced in the N-acetylcystein group (57.1% versus 28.6%, p=0.016). Nonuse of N-acetylcystein (relative risk 3.58, 95% confidence interval: 1.04 to 12.33, p=0.04) and cardiopulmonary bypass (relative risk 4.55, 95% confidence interval: 1.28 to 16.15, p=0.02) were independent predictors of kidney injury. In patients treated with CPB, N-acetylcystein reduced the incidence of kidney injury from 63% to 46%. Oxidative stress was increased in control subjects (p=0.01) and abolished in patients receiving N-acetylcystein. Maximum intravenous doses of N-acetylcystein reduce the incidence of acute kidney injury in patients with kidney disease undergoing coronary artery bypass graft surgery, abolish oxidative stress, and mitigate the negative effect of CPB on renal function.