Abstract Background Patients with atrial fibrillation (AF) have many comorbidities and excess risks of hospitalization and death. Whether the impact of comorbidities on outcomes is greater in AF than the general population is unknown. Methods 1430 AF patients 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. Results 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, AF patients experienced higher rates of hospitalization and death than population controls. However, the impact of comorbidities on hospitalization and death was generally not greater in AF patients compared to 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 to 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. Conclusions 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 AF patients by reducing their risk of adverse outcomes.