Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, necessitating the discovery of novel prognostic biomarkers. Tumor-derived exosomes are emerging as rich reservoirs of protein biomarkers; however, accessing sufficient quantities of tumor-proximal material remains challenging. In this study, we introduce specimen-derived blood (sdBlood), collected immediately after surgical resection of CRC specimens, as a novel and enriched source for tumor-proximal exosome isolation. We employed label-free LC-MS/MS-based proteomics to comprehensively profile the exosomal proteome from sdBlood and compared it with matched peripheral venous blood to identify differentially enriched proteins. Our analyses revealed a distinct proteomic signature in sdBlood-derived exosomes, with several proteins showing significant prognostic potential in publicly available CRC cohorts. This project encompasses the full proteomic dataset generated from these analyses. The data provide a valuable resource for understanding the tumor microenvironment and support the potential of sdBlood as a promising liquid biopsy substrate for prognostic biomarker discovery in colorectal cancer.