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Physical symptoms and depression in heart failure (HF) are key drivers of health-related quality of life (HRQOL). Heart failure self-care behaviors are believed to influence how symptoms affect HRQOL.The goal of this study was to determine if HF self-care behaviors moderate the relationships between physical and depressive symptoms and HRQOL.In a cohort of adults with moderate to advanced HF, multivariate linear regression was used to evaluate the interaction between self-care behaviors (Self-care of HF index maintenance and management scales) and physical HF symptoms (HF Somatic Perception Scale) on emotional HRQOL (emotional dimension of Minnesota Living With HF Questionnaire). The interaction between self-care behaviors and depression (9-item Patient Health Questionnaire) was evaluated on physical HRQOL (physical dimension of Minnesota Living With HF Questionnaire).The mean age of the sample (N = 202) was 57 ± 13 years, 50% were women, and 61% had New York Heart Association class III or IV HF. Controlling for age, Seattle HF score, functional ability, and comorbidities, self-care maintenance and management moderated the relationship between physical HF symptoms and emotional HRQOL. Only self-care maintenance moderated the relationship between depression and physical HRQOL.In HF, HRQOL is dependent on both the severity of physical and depressive symptoms and the level of engagement in HF self-care behaviors. Future research should consider both self-care behaviors and symptoms when examining patient HRQOL.