Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): -) Association for the Promotion of Research on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) -) Ludwig Boltzmann Cluster for Cardiovascular Research BACKGROUND Critically ill patients admitted to an intensive care unit (ICU) exhibit a high mortality rate irrespective of the initial cause of hospitalization. Neprilysin is a neutral endopeptidase degrading an array of vasoactive peptides, including bradykinin, adrenomedullin and natriuretic peptides and became a drug target within the treatment of heart failure with reduced ejection fraction. The aim of this study was to analyze whether circulating levels of neprilysin at ICU admission are associated with 30-day mortality, due to its physiologic effects. METHODS In this single-center prospective observational study, 222 consecutive patients admitted to a tertiary ICU at a university hospital were included. Blood was drawn at admission and soluble neprilysin levels were measured using ELISA. RESULTS Median simplified acute physiology score was 44 and 30-day mortality was 35.1% in medical patients (n = 151) and 7.1% in patients after surgery and heart valve interventions (n = 71). Neprilysin levels did not differ according to survival status after 30 days and admission type. When assessing neprilysin and survival according to admission type, no association was found in medical patients, while in patients after surgery or heart valve intervention, 30-day survivors exhibited significantly lower neprilysin levels as compared to those that died within 30 days (660.2, IQR: 156.4 – 2512.5 pg/ml versus 6532.6, IQR: 1840.1 – 10000.0 pg/ml; p = 0.02). Neprilysin predicted mortality independently from age, gender, NT-proBNP, and SAPS II score (OR per 1-SD increase of neprilysin: 2.52, 95%CI 1.01–6.32; p = 0.049). Additionally, neprilysin was markedly elevated in patients with sepsis and septic shock (p < 0.05). CONCLUSION At the time of ICU-admission, circulating levels of neprilysin independently predicted 30-day mortality in patients following cardiac surgery or heart valve intervention, but not in critically ill medical patients.