Patients with atrial fibrillation (AF) report impaired health-related quality of life (QOL). Differences between men and women with AF have not been described and personality attributes such as somatization (tendency to amplify benign bodily sensations) may mediate potential gender differences in QOL. Patients with AF (n = 264, 59% men) who participated in the Canadian Trial of Atrial Fibrillation (n = 403) completed validated QOL questionnaires at baseline, 3 months, and 12 months after antiarrhythmic drug treatment. Women were significantly older than men and a greater proportion had hypertension, but other cardiac variables did not differ between women and men. At baseline, after controlling for significant clinical and demographic factors, women reported worse physical health (p = 0.002) and functional capacity (p < 0.001), but not mental health or general well-being. Women also had more frequent and severe cardiac symptoms than men (both p < 0.001). Physical health improved significantly from baseline to 3 months for women (p = 0.002), but not for men (p = 0.066). Conversely, mental health improved for men (p = 0.007), but not for women. Cardiac symptom frequency and severity improved over time for women and men (all p < 0.001). Tendency to somatize predicted poor QOL, and women had higher scores than men (p = 0.023). However, after controlling for somatization, women still had worse physical function, functional capacity, and symptom burden than men. Independent of cardiac disease severity and age, women with AF had significantly more impaired QOL than men, specifically on domains related to physical rather than emotional functioning. Personality attributes may have a role in influencing QOL outcomes.