['Most heart failure patients have multiple comorbidities.', 'This study aims to test the moderating effect of comorbidity on the relationship between self-efficacy and self-care in adults with heart failure.', 'Secondary analysis of four mixed methods studies (n = 114) was done. Self-care and self-efficacy were measured using the Self-Care of Heart Failure Index. Comorbidity was measured with the Charlson Comorbidity Index. Parametric statistics were used to examine the relationships among self-efficacy, self-care, and the moderating influence of comorbidity. Qualitative data yielded themes about self-efficacy in self-care and explained the influence of comorbidity on self-care.', 'Most (79%) reported two or more comorbidities. There was a significant relationship between self-care and the number of comorbidities (r = -.25; p = .03). There were significant differences in self-care by comorbidity level (self-care maintenance, F[1, 112], 5.96, p = .019, and self-care management, F[1, 72], 4.66, p = .034). Using moderator analysis of the effect of comorbidity on self-efficacy and self-care, a significant effect was found only in self-care maintenance among those who had moderate levels of comorbidity (b = .620, p = .022, F(change) df[6,48], 5.61, p = .022). In the qualitative data, self-efficacy emerged as an important variable influencing self-care by shaping how individuals prioritized and integrated multiple and often competing self-care instructions.'] Do multiple comorbid conditions challenge heart failure self-care by decreasing self-efficacy?