AIMS: Oxidative stress has recently been implicated in the pathophysiology of atrial fibrillation (AF). The aim of the present study was to evaluate the effects of antioxidant agent N-acetylcysteine (NAC) on postoperative AF. METHODS AND RESULTS: The population of this prospective, randomized, double-blind, placebo-controlled study consisted of 115 patients undergoing coronary artery bypass and/or valve surgery. All the patients were treated with standard medical therapy and were randomized to NAC group (n = 58) or placebo (saline, n = 57). An AF episode >5 min during hospitalization was accepted as endpoint. During follow-up period, 15 patients (15/115, 13%) had AF. The rate of AF was lower in NAC group compared with placebo group (three patients in NAC group [5.2%] and 12 patients in placebo group [21.1%] had postoperative AF; odds ratio [OR] 0.20; 95% confidence interval [CI] 0.05 to 0.77; P = 0.019). In the multivariable logistic regression analysis, independent predictors of postoperative AF were left atrial diameter (OR, 1.18; 95% CI, 1.06-1.31; P = 0.002) and the use of NAC (OR, 0.20; 95% CI, 0.04-0.91; P = 0.038). CONCLUSION: The result of this study indicates that NAC treatment decreases the incidence of postoperative AF.