Updated project metadata. Minimally- invasive diagnostic biomarkers for patients with pancreatic ductal adenocarcinoma (PDAC) and distal cholangiocarcinoma (CCA) are warranted to enhance early and accurate diagnosis. This study identified tumor tissue secreted proteins, the “secretome”, which was analysed for differential candidate diagnostic plasma proteins. Secretome of tumor and normal tissue was collected directly after resection of the primary tumor from 4 patients with PDAC and distal CCA. The tissue secretome was investigated by label-free LC-MSMS, and database searching identified a total of 5179 proteins. 696 proteins were differentially enriched in tumor secretome compared to normal tissue. Thrombospondin-2 (THBS2) emerged as most promising candidate diagnostic biomarker. Subsequent analysis of THBS2 in plasma samples of patients with PDAC and distal CCA by ELISA showed significantly higher abundance compared to healthy individuals (p<0.001) and resulted in an AUC of 0.844.