This study examined the gender and culture differences in relation to the quality of life among Americans and Koreans with atrial fibrillation. It employed secondary data analysis and a descriptive comparative design. The settings were the cardiology outpatient clinics and the outpatient clinic in two urban hospitals in the USA and one university hospital in Korea. The quality of life was measured by the Short-Form Health Survey. The data from 129 subjects were analyzed by two-way ANCOVA and a post-hoc test. In relation to physical function, there was a statistically significant effect shown by gender, but no significant differences were found by the main effect of culture and the interaction effect of gender and culture. The significant interaction effect of gender and culture on mental health was shown. In conclusion, gender differences in the quality of life perceived by patients with atrial fibrillation varied with their cultural background. Thus, patients' cultural background should be considered in nursing practice.