Introduction Postoperative Atrial Fibrillation (POAF) is associated with a higher rate of postoperative complications and mortality, as well as with longer hospitalization and increased treatment costs. We have designed and performed a randomized, trial of pharmacological prophylaxis in which the event of interest is POAF. Aim The aim of this study is to reduce the risk of postoperative, complications associated with this arrhythmia. Methods We included 240 stable patients with a coronary heart disease, who were referred to elective surgical revascularization of the myocardium. The patients were assigned into three groups of 80 patients each: group A (BB, beta blocker, comparator), group B (BB+ Amiodarone) and group C (BB + Rosuvastatin). The goal was to establish whether intervention by combination therapy was more useful than a comparator. Results An event of interest (POAF) has occurred in 66 of the total 240 patients. Number of new POAF cases is the lowest in Group B, 14 (17.5%) compared to 25 (31.25%) new cases in the comparator group, and 27 new cases (33.75%) in group C. Absolute risk reduction was 13.75%, ≈14% less POAF in group B compared to comparator. Relative risk reduction was 56% (RR 0.56, p = 0.04). Number Needed to Treat was 7.27. In group C, 33.75% of patients developed POAF. Absolute risk was insignificantly higher in group C (2.5%, NS) compared to the comparator .The number needed to harm was high, 40. Conclusion The results of our research show that prophylaxis of POAF with combined therapy BB + Amiodarone was the most efficient one.