Atrial fibrillation is the most common complication after open-heart surgery. The incidence rate is 25-50%. This review summarizes findings of economic studies of amiodarone prophylaxis in cardiac surgery patients. Data were pooled from more than 15 studies. Four meta-analyses combining six to 19 amiodarone trials indicated a significant decrease in the incidence of postoperative atrial fibrillation (odds ratio range: 0.50-0.54). Other studies (individual randomized controlled trials, naturalistic studies and economic models) supported this finding. A majority of studies showed that amiodarone prophylaxis was cost neutral and resulted in a decrease in the length of stay, the main cost driver in postoperative atrial fibrillation. Selective use of amiodarone in high-risk patients (over 70 years, history of atrial fibrillation and chronic obstructive pulmonary disease, and concurrent valve surgery) will potentially enhance its cost-effectiveness.