Context: Atrial tachyarrhythmias after cardiac surgery are associated with adverse outcomes and increased costs. Previous trials of amiodarone prophylaxis, while promising, were relatively small and yielded conflicting results. Objective: To determine whether a brief perioperative course of oral amiodarone is an effective and safe prophylaxis for atrial tachyarrhythmias after cardiac surgery overall and in important subgroups. Design, Setting, and Patients: Double-blind randomized controlled trial of 601 patients listed for nonemergent coronary artery bypass graft(CABG) surgery and/or valve replacement/repair surgery between February 1, 1999, and September 26, 2003, at a tertiary care hospital. The patients were followed up for 1 year. Intervention: Oral amiodarone(10 mg/kg daily) or placebo administered 6 days prior to surgery through 6 days after surgery(13 days). Randomization was stratified for subgroups defined by age, type of surgery, and use of preoperative β -blockers. Main Outcome Measure: Incidence of atrial tachyarrhythmias lasting 5 minutes or longer that prompted therapy by the sixth postoperative day. Results: Atrial tachyarrhythmias occurred in fewer amiodarone patients(48/299; 16.1% ) than in placebo patients(89/302; 29.5% ) overall(hazard ratio[HR], 0.52; 95% confidence interval[CI], 0.34- 0.69; P< .001); in patients younger than 65 years(19[11.2% ] vs 36[21.1% ]; HR, 0.51[95% CI, 0.28- 0.94]; P=.02); in patients aged 65 years or older(28[21.7% ] vs 54[41.2% ]; HR, 0.45[95% CI, 0.27- 0.75]; P< .001); in patients who had CABG surgery only(22[11.3% ] vs 46[23.6% ]; HR, 0.45[95% CI, 0.26- 0.79]; P=.002); in patients who had valve replacement/repair surgery with or without CABG surgery(25[23.8% ] vs 44[44.1% ]; HR, 0.51[95% CI, 0.31- 0.84; P=.008); in patients who received preoperative β -blocker therapy(27[15.3% ] vs 42[25.0% ]; HR, 0.58[95% CI, 0.34- 0.99]; P=.03); and in patients who did not receive preoperative β -blocker therapy(20[16.3% ] vs 48[35.8% ]; HR, 0.40[95% CI, 0.22- 0.71]; P<.001), respectively. Postoperative sustained ventricular tachyarrhythmias occurred less frequently in amiodarone patients(1/299; 0.3% ) than in placebo patients(8/302; 2.6% )(P=.04). Dosage reductions of blinded therapy were more common in amiodarone patients(34/299; 11.4% ) than in placebo patients(16/302; 5.3% )(P=.008). There were no differences in serious postoperative complications, inhospital mortality, or readmission to the hospital within 6 months of discharge or in 1-year mortality. Conclusion: Oral amiodarone prophylaxis of atrial tachyarrhythmias after cardiac surgery is effective and may be safe overall and in important patient subgroups. Context: Atrial tachyarrhythmias after cardiac surgery are associated with adverse outcomes and increased costs. Previous trials of amiodarone prophylaxis, while promising, were relatively small and yielded conflicting results. Objective: To determine whether a brief perioperative course of oral amiodarone is an effective and safe Prophylaxis for atrial tachyarrhythmias after cardiac surgery overall and in important subgroups. Design, Setting, and Patients: Double-blind randomized controlled trial of 601 patients listed for nonemergent coronary artery bypass graft (CABG) surgery and / or valve replacement / repair surgery between February 1, 1999, and September 26, 2003, at a tertiary care hospital. The patients were followed up for 1 year. Intervention: Oral amiodarone (10 mg / kg daily) or placebo administered 6 days prior to surgery through 6 days after surgery ( 13 days). Randomization was stratified for subgroups defined by age, type of surgery, and use of preoperative β-blockers. Main Ou tcome Measure: Incidence of atrial tachyarrhythmias lasting 5 minutes or longer that prompted therapy by the sixth postoperative day. Results: Atrial tachyarrhythmias occurred in fewer amiodarone patients (48/299; 16.1%) than in placebo patients (89/302; 29.5%) (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.34- 0.69; P <.001); in patients younger than 65 years (19 [11.2%] vs 36 [21.1%]; HR, 0.51 ; In patients aged 65 years or older (28 [21.7%] vs 54 [41.2%]; HR, 0.45 [95% CI, 0.27- 0.75]; P Inpatients who had CABG surgery only (22 [11.3%] vs 46 [23.6%]; HR, 0.45 [95% CI, 0.26-0.79]; P = .002) / repair surgery with or without CABG surgery (25 [23.8%] vs 44 [44.1%]; HR, 0.51 [95% CI, 0.31-0.84; P = .008); in patients who received preoperative [beta] -blocker therapy (15.3%) vs 42 (25.0%); HR, 0.58 [95% CI, 0.34-0.99]; P = .03); and in patients who did not receive preoperative beta -blocker therapy (20 [16.3%] vs 48 [35Postoperative sustained ventricular tachyarrhythmias less frequent in amiodarone patients (1/299; 0.3%) than in placebo patients (8%; HR, 0.40 [95% CI, 0.22-0.71]; P <.001) (P = .04). Dosage reductions of blinded therapy were more common in amiodarone patients (34/299; 11.4%) than in placebo patients (16/302; 5.3% . There were no differences in serious postoperative complications, inhospital mortality, or readmission to the hospital within 6 months of discharge or in 1-year mortality. Conclusion: Oral amiodarone prophylaxis of atrial tachyarrhythmias after cardiac surgery is effective and may be safe overall and in important patient subgroups.