Estimates from clinical trials and small observational studies of the incidence of pulmonary toxicity (PT) associated with amiodarone range from 1% to 10%. We report a unique study of the population-based incidence and potential predictors of PT in a real-world atrial fibrillation (AF) population. We conducted a retrospective cohort study of patients =65 years old discharged with AF using linked administrative databases from Quebec, Canada from 1999 to 2007. "Users" and "nonusers" of amiodarone were identified by prescriptions dispensed within 7 days after hospital discharge. PT was defined through International Classification of Diseases, Ninth Revision and Tenth Revision codes for pulmonary fibrosis, alveolar/interstitial lung disease, and adult respiratory distress syndrome. Potential risk factors for PT were identified using multivariable Cox regression. PT occurred in 250 of 6,460 amiodarone users (3.87%) and 676 of 50,993 nonusers (1.33%). Age-standardized PT incidences were 28.30 and 16.02 per 1,000 person-years in men and women users, respectively, and 14.05 and 8.82 per 1,000 person-years in nonusers, respectively. It was associated with amiodarone exposure at all doses (=200 mg/day, hazard ratio 1.62, 1.35 to 1.96; >200 mg/day, 1.46, 1.22 to 1.75). Other predictors of PT included increasing age (1.01 per year, 1.00 to 1.02), male gender (1.37, 1.19 to 1.57), chronic obstructive pulmonary disease (2.53, 2.21 to 2.89), and renal disease (1.26, 1.06 to 1.50). In conclusion, the population-based incidence of amiodarone PT is in the lower range of what has been previously reported. However, patients with AF who use amiodarone have an approximately 50% higher risk of PT than nonusers. Clinicians may be able to use the present results to identify patients at higher risk for PT and implement strategies to increase monitoring or select alternative therapy.