No published studies have evaluated the risks of cardiovascular (CV) events, stroke, congestive heart failure (CHF), interstitial lung disease (ILD), and severe acute liver injury (ALI) related to antiarrhythmics treatment in real-world clinical practice setting. We examined the relationship between the above events and the selected antiarrhythmics in the real-world setting in the US. Using a retrospective cohort design, the hazard ratios of the outcome events were analyzed from 10,455 adult patients with a diagnosis of atrial fibrillation/atrial flutter and a new treatment with dronedarone (reference drug), amiodarone, sotalol, flecainide, or propafenone between 07/20/2009 and 12/31/2010 from the Clinformatics Data Mart database. The patients were followed until: 1) switch to another antiarrhythmic drug, 2) occurrence of the outcome event, 3) end of enrollment, or 4) end of the study period, whichever occurred first. No significant differences were observed in the hazard ratios of the outcome events between dronedarone, amiodarone, and the other antiarrhythmics, except that amiodarone was associated with a higher risk of CV events (adjusted HR = 2.3, 95%CI: 1.8-2.9), stroke (adjusted HR = 2.4, 95%CI: 1.5-3.8), and CHF (adjusted HR = 2.6, 95%CI: 2.3-2.9) compared to dronedarone, especially amongst patients without a CHF history. In this real-world investigation, the results indicated that dronedarone could be an alternative therapy option with lower CV risk than amiodarone in patients with atrial fibrillation/atrial flutter (AF/AFL).