Here, we report that defensin-rich platelets (DRPs) promote proliferation, migration, and spheroid growth of pancreatic cancer cells, upregulate key aggressiveness-related genes, and are associated with adverse clinical outcomes, supporting the concept that platelet-derived DEFA1/3 represents a functional driver for PDAC progression and a candidate for translational exploration as a biomarker or therapeutic target. Here, DEFA1 is linked to pancreatic neoplasm.