Background: A range of neurohumoral substances have been suggested as diagnostic markers in heart failure. It is, however, undetermined which marker has the greatest diagnostic potential, and whether additional information is gained by a comprehensive neurohumoral evaluation. Aims: The purpose of the study was to compare the value of epinephrine, norepinephrine, renin activity, aldosterone (ALDO), atrial (ANP) and brain (BNP) natriuretic peptides, arginine-vasopressin and endothelin (ENDO) as markers for left ventricular (LV) dimensions and ejection fraction (LVEF) in patients with systolic heart failure. Methods: Forty-eight patients with symptomatic heart failure were examined with blood samples and magnetic resonance imaging along with 20 age and gender-matched normal controls. Results: In multiple regression analyses, BNP was the strongest independent marker for LV end-diastolic (r = 0.71, P < 0.0001), and end-systolic (r = 0.75, P < 0.0001) volumes, myocardial mass (r = 0.69, P < 0.0001), and LVEF (r = - 0.78, P < 0.0001). ANP was a supplementary independent marker for LV end-diastolic (r = 0.76, P < 0.0001) and end-systolic (r = 0.78, P < 0.0001) (ANP and BNP combined) volumes, ENDO for myocardial mass [r = 0.71, P < 0.0001 (ENDO/BNP)], and ALDO for LVEF [r = -0.81, P < 0.0001 (ALDO/BNP)]. Conclusion: BNP is the strongest marker for LV dimensions and LVEF in patients with systolic heart failure. However, a comprehensive neurohumoral evaluation may add some information to the diagnosis.