Background: Chromogranin B (CGB) regulates B-type natriuretic peptide (BNP) production. Circulating CGB levels are elevated in heart failure (HF) animal models and HF patients, but also increase in healthy individuals in response to physical activity. Therefore, CGB seems to integrate information from myocardial stress and systemic neuro-endocrine activation. Substantial gaps remain in our understanding of CGB regulation in HF. Methods and results: We conducted a retrospective registry study including 372 patients. CGB and N-terminal pro-BNP (NT-proBNP) plasma levels were assessed in acute HF and chronic valvular HF patients and controls. CGB levels were significantly increased in acute HF and chronic valvular HF, but significantly higher in the latter. Patients in chronic valvular HF with severe mitral regurgitation (cHF-MR) showed significantly higher CGB levels than patients in chronic valvular HF with severe aortic stenosis. CGB levels progressively increased with worsening NYHA functional status and were moderately correlated to NT-proBNP, but independent of left ventricular (LV) ejection fraction (LVEF), LV mass, age and body weight. Finally, cHF-MR patients showed significant reductions of CGB levels after interventional mitral valve repair. Conclusion: CGB is a promising emerging biomarker in HF patients with unique potential to integrate information from myocardial stress and neuro-endocrine activation.