Background: Atrial fibrillation (AF) is one of the most common arrhythmias after coronary artery bypass graft (CABG) surgery. AF can result in hemodynamic instability, thromboembolic events, increase the perioperative myocardial infarction, congestive heart failure, stroke, more length of hospital stay (LOHS) and cost of treatment. The aim of this study was to evaluate the independent effect of digoxin in preventing AF after CABG in patients who had a predictor for AF and had already been on other anti-arrhythmic drugs. Methods: In a prospective randomized clinical trail, using alternate randomization, 239 patients categorized into three different groups. Group one consisted of 72 patients who had at least one predictor for developing AF after CABG. Group two consisted of 67 patients with the same predictors who received 0.5 mg intravenous digoxin after disconnecting from bypass pump followed by 0.25 mg intravenous digoxin one hour and four hours later. Oral daily digoxin (0.25 mg) was continued from the first post operation day to the 14th day with 2 days off per week. One hundred patients without those predictors for AF were randomly allocated in group three to confirm the impact of those predictors on developing AF. Results: AF occurred in 16 patients (22.2%) in group 1, six patients (8.8%) in group 2, and seven patients (7%) in group 3. The duration of AF was 6.43±4.23 min in group 1, 1.2±1.41min in group 2, and 47.18±67.29 min in group 3. Conclusion: Intraoperative digoxin can independently decrease the incidence of AF after CABG surgery in patients with high risk factors for AF.