Abstract Body (Do not enter title and authors here): Background: Heart failure (HF) is a condition frequently complicated by renal dysfunction, which can significantly impair patients' health-related quality of life (HRQoL). Although the relationship between renal dysfunction and HRQoL in HF is well-documented, the mechanisms underlying this association remain unclear. Patient-centered outcomes (PCOs), including depressive symptoms, functional status, adherence to recommended self-care strategies, and self-care behaviors may mediate this relationship. We aimed to examine the mediating effects of PCOs on the relationship between renal dysfunction and HRQoL in patients with HF. Methods: A secondary analysis was conducted using data from 516 patients (61 ± 13 years) in the Research and Interventions for Cardiovascular Health (RICH) Heart Program Database. Depressive symptoms (Patient Health Questionnaire-9), functional status (Duke Activity Status Index), adherence to recommended self-care strategies (Medical Outcomes Study Specific Adherence Scale), self-care behaviors (Self-Care of Heart Failure Index), and HRQoL (Minnesota Living with Heart Failure Questionnaire) were assessed. The PROCESS macro (Model 4) was used to determine the indirect effects of renal dysfunction on HRQoL. Results: Renal dysfunction had significant indirect effects on HRQoL through depressive symptoms (Indirect effect = 3.62, SE = 1.25, 95% Bootstrap Confidence Interval [CI]:1.25 to 6.25) and functional status (Indirect effect = 6.21, SE = 1.78, 95% Bootstrap CI: 3.37 to 10.49), controlling for age and gender. Having renal dysfunction was associated with increased depressive symptoms and decreased functional status, which were then associated with decreased HRQoL. Conclusions: Our findings indicate that renal dysfunction can lead to worse HRQoL by increasing depressive symptoms and decreasing functional status in patients with HF. Interventions targeting these factors may improve HRQoL in this population.