OBJECTIVE: New biomarkers are needed to better predict the severity of acute pancreatitis. CD73/ecto-5'-nucleotidase is an enzyme that generates adenosine, which dampens inflammation and improves vascular barrier function in several disease models. CD73 also circulates in a soluble form in the blood. We studied whether levels of soluble form of CD73 predict the development of organ failure in acute pancreatitis. DESIGN: A prospective cohort study of patients with acute pancreatitis from 2003 to 2007. SETTING: Admissions to the biggest tertiary care hospital in Finland. PATIENTS: One hundred sixty-one patients with acute pancreatitis, of which 107 were subclassified according to the revised Atlanta criteria into mild, 29 into moderately severe and 25 into severe. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Serum and blood cell samples were collected at admission. Protein levels of soluble form of CD73 in serum were determined using a novel enzyme-linked immunosorbent assay, activity of soluble form of CD73 using radioactive enzyme assays, and CD73 messenger RNA levels from leukocytes using quantitative polymerase chain reaction. Activity and protein concentration of soluble form of CD73, and messenger RNA level of CD73 all decreased along with the disease severity (p