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Circulating soluble neprilysin, an endopeptidase that catalyses the degradation of various endogenous vasodilators, predicts outcome in patients with heart failure and reduced ejection fraction (HFrEF). In the present study, we measured for the first time circulating soluble neprilysin in a prospective cohort of patients with heart failure with preserved ejection fraction (HFpEF) and correlated the serum levels to outcome, functional markers, established risk factors for HFpEF, myocardial fibrosis assessed by cardiac magnetic resonance (CMR) imaging, as well as histological data obtained by myocardial biopsy and various invasive haemodynamic measurements.We prospectively included 144 consecutive patients with HFpEF in our observational, non-interventional registry. Echocardiography, CMR imaging, and invasive haemodynamic assessments including myocardial biopsy were performed at baseline. We did not observe a significant association between soluble neprilysin levels and hospitalization for heart failure and/or death in the Cox regression analysis (P = 0.56). Furthermore, there were no significant differences between tertiles of neprilysin in outcome, functional markers, established risk factors for HFpEF, CMR measurements including post-contrast T1 time, extracellular matrix obtained by myocardial biopsy, and invasive haemodynamic measurements. NT-proBNP demonstrated a weak correlation with levels of soluble neprilysin (r = − 0.26, P = 0.002).Our results describe for the first time circulating levels of soluble neprilysin in patients with HFpEF. In contrast to HFrEF, we could not confirm an association between neprilysin levels and cardiovascular mortality or hospitalization for heart failure.