ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer, with a five-year survival rate of less than 10%. In South Africa, PDAC was the seventh leading cause of cancer deaths among men and the sixth among women in 2020. Approximately 85% of patients are diagnosed at an advanced stage, highlighting the urgent need for ongoing research to identify reliable biomarkers that could improve clinical outcomes. Circulating proteins are present not only as soluble molecules but also encapsulated within extracellular vesicles (EVs), which protect and transport biologically active cargo in plasma. This study compared the plasma proteomes of patients with PDAC with those of patients with benign biliary pathologies (BBP) and healthy controls (HC). We employed Mag-Net, a magnetic bead-based method that combines the enrichment of membrane-bound vesicles with the depletion of high-abundance plasma proteins. On average, 2,339 protein groups were identified across all sample groups. Comparative analyses revealed both unique and overlapping dysregulated proteins among the PDAC, BBP, and HC cohorts. PDAC was characterised by coordinated extracellular matrix (ECM) remodelling, chronic immune-inflammatory activation, and metabolic disruption, particularly affecting lipid homeostasis. This molecular profile was marked by elevated ECM-associated and matricellular proteins (such as THBS2, TGFBI, MFAP4, ANPEP, and ITIH4) alongside increased inflammatory mediators (including ORM1, C1QC, CTSS, SPP1, FBLN2, LTBP2, SDC1, HP, SAA1, PTX3, and LRG1). This overlap suggests that dynamic ECM remodelling within the tumour microenvironment is mirrored systemically by the release or shedding of matrix-associated proteins into the circulation. Notably, LRG1 demonstrated the strongest association with disease severity and clustered with acute-phase proteins, complement components, and pancreatic injury markers, supporting its role within an inflammation-stromal remodelling network characteristic of aggressive PDAC. Collectively, these findings demonstrate that plasma proteomics provides valuable discriminatory and severity-related information. While several candidate proteins show promise for inclusion in multi-analyte panels, further validation in larger, independent cohorts is necessary to establish their diagnostic and translational utility for early detection, risk stratification, and improved differential diagnosis of PDAC.