Objective We investigated the relationship between anxiety and event-free survival (ie, composite endpoint of death, emergency department visits, or hospitalizations) for patients with heart failure (HF), and examined whether behavioral and physiologic mechanisms mediate any association between anxiety and outcomes. Methods In this longitudinal study, patients with HF completed the anxiety subscale of the Brief Symptom Inventory, and heart-rate variability and plasma norepinephrine levels were measured. Dietary adherence and medication adherence were measured according to 24-hour urine sodium level and the Medication Event Monitoring System, respectively. Patients were followed at least 1 year for event-free survival. Results In total, 147 patients were enrolled. Patients with high anxiety had a shorter (hazard ratio, 2.2; 95% confidence interval, 1.1-4.3; P = .03) period of event-free survival than patients with lower anxiety. Anxiety independently predicted adherence to medication (P = .008), which in turn predicted event-free survival (hazard ratio, 2.0; 95% confidence interval, 1.2-3.3; P = .008). The effect of anxiety (P = .17) on event-free survival was less significant when the regression model included both anxiety and adherence to medication than when the model only included anxiety (P = .03), indicating that adherence to medication mediated the relationship between anxiety and event-free survival. Conclusion This is the first study to show that nonadherence to medication links anxiety and event-free survival for patients with HF. Interventions that reduce anxiety and improve adherence may benefit outcomes.