Objective: This study investigated gender differences, depression, and health-related quality of life (QoL) in a crosssectional sample of patients with atrial fibrillation (AF). Methods: This cross-sectional study involved a convenience sample of AF patients from two tertiary-care clinics in Toronto, Canada. Ninety-three AF patients completed psychometrically validated measures of generic QoL and depression. Mediation analyses evaluated the relationship between gender and QoL using depression as mediating variable. Results: Relative to male patients, female patients reported lower physical, but not mental, QoL. Gender was associated with both depression and physical QoL, while depression was correlated with poorer physical QoL. Path analyses demonstrated that depression significantly mediated the relationship between gender and physical QoL. Conclusion: Among AF patients, female patients report lower physical QoL relative to male patients, and this relationship may be mediated by self-reported symptoms of depression. Albeit correlational, the findings underscore the need to develop a better understanding of the role of depression in physical QoL, especially when considering the burden of AF in women. D