One thousand four hundred thirty patients with AF and community controls matched 1:1 on age and sex were obtained from Olmsted County, Minnesota. Andersen-Gill and Cox regression estimated associations of 19 comorbidities with hospitalization and death, respectively. AF cases had a higher prevalence of most comorbidities. Hypertension (25.4%), coronary artery disease (17.7%), and heart failure (13.3%) had the largest attributable risk of AF; these along with obesity and smoking explained 51.4% of AF. Over a mean follow-up of 6.3 years, patients with AF experienced higher rates of hospitalization and death than did population controls. However, the impact of comorbidities on hospitalization and death was generally not greater in patients with AF compared with controls, with the exception of smoking. Ever smokers with AF experienced higher-than-expected risks of hospitalization and death, with observed vs expected (assuming additivity of effects) hazard ratios compared with never smokers without AF of 1.78 (1.56-2.02) vs 1.52 for hospitalization and 2.41 (2.02-2.87) vs 1.84 for death. Patients with AF have a higher prevalence of most comorbidities; however, the impact of comorbidities on hospitalization and death is generally similar in AF and controls. Smoking is a notable exception; ever smokers with AF experienced higher-than-expected risks of hospitalization and death. Thus, interventions targeting modifiable behaviors may benefit patients with AF by reducing their risk of adverse outcomes.