Objective: Heart failure affects more than 5 million U.S. adults, and approximately 20% of individuals with heart failure experience depressive symptoms. Depression is detrimental to prognosis in heart failure, conferring approximately a 2-fold increase in mortality risk. Medication nonadherence may help explain this relationship because depressed patients are less likely to adhere to the medication regimen. Method: Depression, electronically monitored medication adherence, and mortality were measured in a sample of 308 patients with heart failure participating in a study of self-management behavior. Cardiovascular and all-cause mortality data were obtained from the Centers for Disease Control and Prevention’s National Death Index (median 2.9-year follow-up). Cox proportional hazards regression was used to assess the relationship between depression and mortality, with and without adjustment for age, gender, disease severity, and medication nonadherence. Results: In adjusted analyses, depression was associated with an increased all-cause mortality risk (hazard ratio 1.87; 95% confidence interval 1.04–3.37). Depression was not related to cardiovascular mortality, potentially because of a low number of cardiac-related deaths. When medication nonadherence was added to the model, nonadherence (hazard ratio 1.01; 95% confidence interval 1.004–1.02), but not depression, predicted all-cause mortality risk. Conclusions: Depressive symptoms confer increased all-cause mortality risk in heart failure, and medication nonadherence contributes to this relationship. Depression and nonadherence represent potentially modifiable risk factors for poor prognosis. Future research is needed to understand whether interventions that concomitantly target these factors can improve outcomes.