Healthcare providers should be concerned with improving the quality of life (QOL) of patients with heart failure (HF) because disease-specific QOL is linked to disease progression. The present study investigated the significance of elevated b-type natriuretic peptide (BNP), NYHA classification and depression to HF-related QOL to develop better management strategies. Outpatient subjects with left ventricular systolic dysfunction (n=108; mean age=64.9±12) completed the self-administered Minnesota Living with Heart Failure questionnaire and the Center for Epidemiologic Studies Depression Scale. Functional status was measured using the New York Heart Association Classification (NYHA) and BNP concentrations were measured in plasma samples. Multiregression analysis determined that plasma BNP levels did not contribute significantly to the total QOL score while depression (r=0.63, t ratio=7.43, P<.0001) and NHYA class (r=0.47, t ratio=3.31, P<.001) were significant contributors. NYHA III subjects exhibited worse depression scores (II 15±7 and III: 22±10, P<.001) and elevated plasma BNP (II: 2.0±0.5 and III: 2.4±0.6, P<.001). Low-cost psychological assessments are recommended to evaluate depression and suggest that those HF patients with NYHA III be closely monitored for depression and reduced QOL.