Background Comorbidity is associated with decreased confidence or self-efficacy to perform self-care in heart failure patients which, in turn, impairs self-care behaviors. Comorbidity is also associated with increased hospitalization rates and poorer quality of life. Yet the manner in which comorbidity and self-efficacy interact to influence self-care, hospitalization, and quality of life remains unclear. Objectives The purpose of this study was to test an explanatory model. The research questions were (1) What is the contribution of comorbidity to heart failure self-care behaviors and outcomes (i.e. hospitalization, quality of life)? and (2) Is comorbidity a moderator of the relationship between self-efficacy and heart failure self-care behaviors? Design This was an analysis of an existing dataset of 628 symptomatic, older (mean age = 73, standard deviation (SD) = 11) male (58%) Italian heart failure patients using structural equation modeling and simple slope analysis. Results Higher levels of self-care maintenance were associated with higher quality of life and lower hospitalization rates. Higher levels of comorbidity were associated with lower levels of self-care management. Comorbidity moderated the relationship between self-efficacy and self-care maintenance, but not self-care management. Post hoc simple slopes analysis showed significantly different slope coefficients (pdiff < .05). Specifically, in patients with less comorbidity, the relationship between self-efficacy and self-care was significantly stronger than in patients with higher comorbidity. Conclusions Self-efficacy is important in the self-care maintenance process at each level of comorbidity. Because higher comorbidity weakens the strength of the relationship between self-efficacy and self-care maintenance, tailoring interventions aimed at improving self-efficacy to different levels of comorbidity may be key to impacting hospitalization and quality of life.