Background: Multiple studies have shown that amiodarone is effective in treating atrial fibrillation (AF), but is associated with a relatively high incidence of side effects; however, due to amiodarone's long elimination half-life (20100 days), physicians may hesitate to start other drugs until it has fully cleared. Hypothesis: A rapid switch from amiodarone to dronedarone is feasible. Methods: EURIDIS and ADONIS were double-blind, multinational, parallel-group trials comparing the efficacy and safety of dronedarone with placebo over 12 months. This retrospective subanalysis of EURIDIS/ADONIS compared the effects of dronedarone in patients discontinuing amiodarone within 2 days before randomization (rapid switch) with results in patients who had received no amiodarone during the 2 months preceding randomization. Results: In total, 1237 patients were enrolled (rapid switch, n = 154; no amiodarone, n = 1014). In both the rapid switch and the no amiodarone groups, dronedarone users had significantly lower AF recurrence than patients receiving placebo (HR = 0.64, 95% CI, 0.440.95; P = 0.0224 and HR = 0.79, 95% CI, 0.670.92; P = 0.0027, respectively). Dronedarone users had a higher incidence of bradyarrhythmic events than placebo-treated patients. A rapid switch from amiodarone to dronedarone was associated with a higher incidence of serious heart failure events and heart failure hospitalizations versus all other groups. Overall event rates were low and there was no significant difference in total adverse event rates or deaths between groups. Conclusion: In this patient population, a switch from amiodarone to dronedarone within a 2-day time frame might be feasible in certain patient categories, but further investigation is warranted. The ADONIS/EURIDIS studies and this post hoc analysis were funded by sanofi-aventis. The authors have no other funding, financial relationships, or conflicts of interest to disclose.