Objectives: S100A8/A9 expression has been linked to carcinogenesis and inflammation. We hypothesized that S100A8/A9 protein serum levels are a useful stratification marker for patients with pancreatic ductal adenocarcinoma (PDAC), intraductal papillary mucinous neoplasm (IPMN) or chronic pancreatitis (CP).Methods: S100A8/A9 serum levels were analysed in PDAC, CP and IPMN patients and compared to S100A8/A9 healthy donor controls (HD) using ELISA. S100A8/A9 levels and clinical data were statistically analysed.Results: Out of 134 patients included, 84 were diagnosed with PDAC (46%), 30 patients with IPMN (16%) and 20 patients with CP (11%), 50 patients were HD (27%). When compared to HD (343.3 ng/ml), S100A8/A9 serum concentration was elevated in PDAC (402.0 ng/ml, p = 0.001) and CP patients (426.51 ng/ml p < 0.001). Also, S100A8/A9 levels were elevated in PDAC compared to IPMN group (369.0 ng/ml p = 0.026) and in CP compared to IPMN group (p = 0.001). A multivariate model including age, gender, leukocyte levels, C-reactive protein (CrP), S100A8/A9 and CA 19-9 concentrations reported a diagnostic sensitivity of 74.8%.Conclusion: S100A8/A9 serum levels are increased in patients with PDAC, CP, and IPMN and might be useful to distinguish malignant and inflammatory diseases from normal and non-malignant pathological conditions.