OBJECTIVES: :  Hospitalization is recognized as an important endpoint in atrial fibrillation (AF) clinical trials. The association between hospitalization and reduced health-related quality of life (HRQOL) has not been studied. Therefore, a large AF registry was used to characterize the impact of hospitalization on HRQOL. METHODS: The FRACTAL study was an observational registry of patients enrolled in the United States and Canada with new-onset AF. HRQOL was assessed with the SF-12 and the AF Symptom Checklist at baseline, 3, 6, and 12, 24 and 30 months. Mixed linear regression models were fitted to estimate the impact of hospitalization on HRQOL summary scores (physical and mental component scores of SF-12, symptom frequency and severity, and utilities from the SF-12), adjusting for demographic and clinical variables known to influence HRQOL in this population. RESULTS: Of 933 subjects who completed HRQOL questionnaires and were not hospitalized during the baseline study visit, 303 (32%) were hospitalized a total of 490 times during an average of 2.0 years of follow-up. The majority (64%) of these admissions were for cardiovascular causes. The adjusted effect of any hospital admission (vs. none) on symptom frequency and severity scores over time was +1.3 and +1.1 points, respectively (p<0.01 for both), with higher scores indicating greater symptom burden. The adjusted effect of any admission on the SF-12 physical score was -2.7 points (p<0.0001) and a decrement on utility of 0.03 (p<0.0001).  In contrast, hospitalization had little effect on longitudinal SF-12 mental scores (-0.7 points, p=0.15). CONCLUSIONS: In a real life long term AF registry, hospitalizations during follow-up were associated with significant increases in AF symptoms and decrements in generic physical HRQOL and utilities. Based on these results which may be limited by the study design, interventions that reduce hospital admissions in AF patients would be expected to improve or preserve HRQOL.