AIMS: To examine the risk of death associated with antiarrhythmic drug (AAD) therapy in a nationwide unselected cohort of patients with atrial fibrillation (AF). METHODS AND RESULTS: All patients admitted with AF in Denmark from 1995 to 2004 and their subsequent use of AADs were identified by individual-level linkage of nationwide registries. Multivariable Cox proportional-hazard models with time-dependent covariates were used to analyse the risk of death associated with AAD therapy. A total of 141,500 patients were included in the study; of these 3356 (2.4%) patients received treatment with flecainide, 3745 (2.6%) propafenone, 23,346 (16.5%) sotalol, and 10,376 (7.3%) amiodarone. Annualized mortality rates were 2.54, 4.25, 5.29, and 7.42 per year per 100 person years for flecainide, propafenone, sotalol, and amiodarone, respectively. Multivariable Cox proportional-hazard models did not show increased risk of death associated with any of the AADs. Hazard ratio (95% confidence interval) for flecainide 0.38 (0.32-0.44), propafenone 0.65 (0.58-0.71), sotalol 0.65 (0.63-0.67), and amiodarone 0.94 (0.89-1.00). CONCLUSION: In an unselected cohort of patients with AF, antiarrhythmic treatment with flecainide, propafenone, sotalol, or amiodarone was not associated with increased risk of death. From a safety perspective, this indicates appropriate selection of patients for AAD therapy.