Adherence to treatment is crucial to improve outcomes in patients with heart failure. Good social support is associated with better adherence, but the mechanism for this association has not been well-explored. The aim of this secondary analysis was to examine whether self-care confidence mediates the relationship between social support and treatment adherence in heart failure patients hospitalized with acute exacerbation. A total of 157 inpatients with heart failure (63.5±13 years, 73% New York Heart Association class III/IV) were recruited from two hospitals located in urban areas in the USA. Participants completed the Self-Care of Heart Failure Index, the Multidimensional Perceived Social Support Scale, and the Medical Outcomes Study Specific Adherence Scale. A series of regression models were used to determine the mediation relationship. Controlling for marital status and hospital site, social support was associated with adherence ( p=0.03). When self-confidence was included in the model, the effect of social support became non-significant, indicating full mediation of the relationship between social support and adherence by self-care confidence. The indirect effect (0.04) of social support on adherence through self-confidence was significant (95% confidence interval: 0.01-0.09). Heart failure self-care confidence mediated the relationship between social support and treatment adherence. Thus interventions targeting patients' self-care confidence is essential to maximize patients' treatment adherence.