OBJECTIVE To assess the effect of high-dose N-acetylcysteine on renal function in cardiac surgery patients at higher risk of postoperative renal failure. METHODS Multiblind, placebo-controlled, randomized, phase II clinical trial. METHODS Operating rooms and intensive care units of two tertiary referral hospitals. METHODS A total of 60 cardiac surgery patients at higher risk of postoperative renal failure. METHODS Patients were allocated to either 24 hrs of high-dose N-acetylcysteine infusion (300 mg/kg body weight in 5% glucose, 1.7 L) or placebo (5% glucose, 1.7 L). RESULTS The primary outcome measure was the absolute change in serum creatinine from baseline to peak value within the first five postoperative days. Secondary outcomes included the relative change in serum creatinine, peak serum creatinine level, serum cystatin C, and in urinary output. Further outcomes were needed for renal replacement therapy, length of ventilation, and length of stay in the intensive care unit and hospital. Randomization was successful and patients were well balanced for preoperative and intraoperative characteristics. There was no significant attenuation in the increase in serum creatinine from baseline to peak when comparing N-acetylcysteine with placebo (64.5 +/- 91.2 and 38.0 +/- 42.4 mumol/L, respectively; p = .15). Also, there was no attenuation in the increase in serum cystatin C from baseline to peak for N-acetylcysteine compared with placebo (0.45 +/- 0.43 and 0.30 +/- 0.33 mg/L, respectively; p = .40). Likewise, there was no evidence for differences in any other clinical outcome. CONCLUSIONS In this phase II, randomized, controlled trial, high-dose N-acetylcysteine was no more effective than placebo in attenuating cardiopulmonary bypass-related acute renal failure in high-risk cardiac surgery patients.