Background: Dronedarone is a new antiarrhythmic drug used in the treatment of atrial fibrillation (AF). We investigate its efficacy and tolerability in clinical practice. Methods: We identified 208 patients treated with dronedarone for AF at the Northwestern outpatient practice. Charts were reviewed for clinical efficacy and reasons for discontinuation of the drug. Results: The average age was 65.2 ± 10.8 years, 37% females. Paroxysmal, persistent and permanent AF were noted in 46.2%, 51.9%, and 1.9%, respectively. Average ejection fraction was 56.3 ± 9.1%, 12.8% had a history of congestive heart failure, and 10.3% had valvular heart disease. Dronedarone was discontinued in 25 patients after curative catheter or surgical ablation procedure. Of the remaining 183 patients, dronedarone was discontinued in 48.6% after a mean duration of 6.2 ± 6.3 months because of inefficacy (26.2%), side effects (6%), and other reasons (16.4%). For those remaining on dronedarone (n = 94), after a mean of 11.6 ±6.6 months, clinical efficacy (resolution of or patient-reported improvement in symptoms) was noted in 45.4% patients. On dronedarone therapy, 57.4% had no AF on follow-up (overall efficacy of 29.5%). To evaluate efficacy, ECG only or long-term monitoring were performed in 62.7% and 37.3%, respectively, and found no AF in 69.2 and 48.4%, respectively. There were 3 deaths and 2 transient ischemic attacks (TIA) off dronedarone vs. 1 death, 1 TIA and 2 strokes on dronedarone. Conclusions: Dronedarone has a significant discontinuation rate due to both inefficacy and side effects in clinical practice. Nevertheless, it has moderate clinical efficacy and tolerability in an outpatient population of patients with AF.