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It has been highlighted that the pathological alterations within an organ and tissues might be reflected in serum or plasma proteomic\/peptidic patterns. The aim of the study was to follow the changes in the plasma peptides associated to colorectal cancer progression by mass spectrometry. This study included 27 adenoma, 67 CRC (n\u2009=\u200933 I\u2013II stage and n\u2009=\u200934 III\u2013IV stage), 23 liver metastasis from CRC patients and 34 subjects disease\u2010free as controls. For plasma peptides analysis, samples purification was performed on the Nanoporous Silica Chips technology followed by matrix\u2010assisted laser desorption\/ionisation\u2010time of flight analysis. Since the high complexity of the obtained dataset, multivariate statistical analysis, and discriminant pattern recognition were performed for study groups classification. Forty\u2010four of 88 ionic species were successfully identified as fragments of peptides and proteins physiologically circulating in the blood and belonging to immune and coagulation systems and inflammatory mediators. Many peptides clustered into sets of overlapping sequences with ladder\u2010like truncation clearly associated to proteolytic processes of both endo\u2010 and exoproteases activity. Comparing to controls, a different median ion intensity of the group\u2010type fragments distribution was observed. Moreover, the degradation pattern obtained by proteolytic cleavage was different into study groups. This pattern was specific and characteristic of each group: controls, colon tumour disease (including adenoma and CRC), and liver metastasis, revealing a role as biomarker in early diagnosis and prognosis. Our findings highlighted peculiar changes in protease activity characteristic of CRC progression from pre\u2010cancer lesion to metastatic disease. J. Cell. 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