Introduction Dipeptidyl peptidase-3 (DPP3) is a protease involved in the degradation of several cardiovascular mediators. Adrenomedullin (bio-ADM) is a peptide essential for regulation of endothelial barrier function. In different shock-pathologies, both biomarkers are associated with disease severity, organ dysfunction and mortality. Associations with outcome in critically ill COVID-19 patients are unknown. The objectives of the present study were to investigate associations of bio-ADM and “circulating DPP3” (cDPP3) with short-term outcome in critically ill COVID-19 patients (n=80). Methods A multicentre prospective cohort study was performed. The primary end-point was 28-day mortality. Secondary end-points included different severities of acute kidney injury (AKI). Results cDPP3 levels were mainly associated with 28-day mortality; Area under the receiver operating characteristics (AUROCs) of 0.69 (0.56–0.82, p=0.023), 0.77 (0.64–0.90, p