Depression frequently co-occurs in heart failure (HF) patients, causing significant interference and negative health outcomes. This case-controlled study explored the construct of illness intrusiveness and examined its relationship to HF severity and depression. Older veterans (n = 104) with an HF diagnosis completed a one-time assessment that included demographics, depressive symptoms (Geriatric Depression Scale), the Illness Intrusiveness Rating Scale (IIRS), and HF quality of life and functional abilities (Kansas City Cardiomyopathy Questionnaire [KCCQ]). Analyses included exploratory correlations between IIRS and KCCQ items, a confirmatory factor analysis (IIRS), and formal mediational analyses. Results indicated that the IIRS had adequate internal consistency and concurrent validity, with support for its established three-factor model. Regression analyses indicated that illness intrusiveness mediated HF illness severity and depression. In conclusion, illness intrusiveness may be a better indicator of depression than illness severity (HF symptoms); thus research methods and interventions targeted at reducing illness intrusiveness merit further investigation.