Background: Self-care is believed to improve heart failure (HF) outcomes, but the mechanisms by which such improvement occurs remain unclear. Methods: We completed a secondary analysis of cross-sectional data collected on adults with symptomatic HF to test our hypothesis that effective self-care is associated with less myocardial stress and systemic inflammation. Multivariate logistic regression modeling was used to determine if better HF self-care reduced the odds of having serum levels of amino-terminal pro-B-type natriuretic peptide and soluble tumor necrosis factor α receptor type 1 at or greater than the sample median. Heart failure self-care was measured using the Self-care of Heart Failure Index. Results: The sample (n = 168) was predominantly male (65.5%), and most (50.6%) had New York Heart Association III HF (mean left ventricular ejection fraction, 34.9% [SD, 14.0%]); mean age was 58.8 (SD, 11.5) years. Self-care management was an independent factor in the model (block χ2 = 14.74; P = .005) after controlling for pertinent confounders (model χ2 = 52.15; P < .001). Each 1-point increase in self-care management score (range, 15-100) was associated with a 12.7% reduction in the odds of having levels of both biomarkers at or greater than the sample median (adjusted odds ratio, 0.873; 95% confidence interval, 0.77-0.99; P = .03). Conclusion: Better self-care management was associated with reduced odds of myocardial stress and systemic inflammation over and above pharmacological therapy and other common confounding factors. Teaching HF patients early symptom recognition and self-care of symptoms may decrease myocardial stress and systemic inflammation.