Poor self-care is common among adults with heart failure and leads to poor health outcomes. Low self-efficacy, depression, and low social support are associated with poor self-care, but knowledge about these relationships in heart failure is limited. Secondary data analysis of cross-sectional data from 346 adults with heart failure measuring self-efficacy, depressive symptoms, social support, and self-care adherence was conducted. Tests of mediation using multiple linear regressions indicate that self-efficacy fully mediates the relationships between depression and adherence, and social support and adherence. Bolstering self-efficacy may have a greater impact on self-care adherence than targeting either depression or social support alone.