Abstract Objective: The purpose of this study was to evaluate the safety and efficacy of postoperative administration of prophylactic amiodarone in the prevention of new-onset postoperative atrial fibrillation in patients undergoing coronary artery bypass grafting. Methods In this prospective study 157 patients were randomly divided into two groups: 77 patients (amiodarone group) received intravenous amiodarone in a dose of 10 mg/kg/d for postoperative 48 hours. On postoperative day 2 oral amiodarone was started with a dose of 600 mg/d for 5 days, 400 mg/d for the following 5 days, and 200 mg/d for 20 days, and 80 patients received placebo (control group). Results Preoperative patient characteristics and operative variables were similar in the two groups. Postoperative atrial fibrillation occurred in 8 patients (10.4%) receiving amiodarone and in 20 (25.0%) patients receiving placebo ( P = .017). Duration of atrial fibrillation was 12.8 ± 4.8 hours for the amiodarone group compared with 34.7 ± 28.7 hours for the control group ( P = .003). The maximum ventricular rate during atrial fibrillation was slower in the amiodarone group than in the control group (105.9 ± 19.1 beats per minute and 126.0 ± 18.5 beats per minute, respectively, P = .016). The two groups had a similar incidence of complication other than rhythm disturbances (20.8% vs 20.0%, P = .904). Amiodarone group patients had shorter hospital stays than that of control group patients (6.8 ± 1.7 days vs 7.8 ± 2.9 days, P = .014). The in-hospital mortality was not different between two groups (1.3% vs 3.8, P = .620). Conclusions Postoperative intravenous amiodarone, followed by oral amiodarone, appears to be effective in the prevention of new-onset postoperative atrial fibrillation. It also reduces ventricular rate and duration of atrial fibrillation after coronary artery bypass grafting. It is well tolerated and decreases the length of hospital stay.