Abstract Objective Management of depression, if it is independently associated with repeated hospitalizations for heart failure (HF), offers promise as a viable and cost-effective strategy to improve health outcomes and reduce health care costs for HF. The objective of this study was to assess the association between depression and the number of HF-related hospitalizations in patients with low-to-moderate systolic or diastolic dysfunction, after controlling for illness severity, socioeconomic factors, physician adherence to evidence-based medications, patient adherence to HF drug therapy, and patient adherence to salt restrictions. Methods and Results The Heart Failure Adherence and Retention Trial (HART) was a randomized behavioral trial to evaluate whether patient self-management skills coupled with HF education improved patient outcomes. Depression was measured at baseline with the Geriatric Depression Scale (GDS). The number of hospitalizations was analyzed with a negative binomial regression model that included an offset term to account for the differential duration of follow-up for individual subjects. The average unadjusted number of hospitalizations per year was 0.40 in the depressed group (GDS ≥10) and 0.33 in the nondepressed group (GDS <10). Depression was a strong predictor (incident rate ratio 1.45; P  = .006) after adjusting for physician adherence to evidence-based medication use, patient adherence to HF drug therapy, patient adherence to salt restriction, illness severity, HF severity (6-minute walk <620 feet), and socioeconomic factors. Conclusions Depression is a strong psychosocial predictor of repeated hospitalizations for HF. Compared with nondepressed individuals, those with depression were hospitalized for HF 1.45 times more often, even after controlling for physician adherence to evidence-based medications and patient adherence to HF drug therapy and salt restrictions. This finding suggests that clinicians should screen for depression early in the course of HF management.