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Familial adenomatous polyposis (FAP) is one of the most important clinical forms of inherited susceptibility to colorectal cancer. So far, no accepted prognostic markers are present to monitor patients with FAP. Consequently, the major problem in managing patients with FAP is the difficulty to predict when the switch between adenoma and malignant carcinoma occurs, leading to the necessity of preventive surgery. Proteomics is one of the most suitable approaches to identify biomarkers, and it is widely used in cancer research. In this investigation, we studied the circulating plasma peptides in samples collected from patients with FAP and compared the obtained results with adenoma, colorectal cancer, and control samples to discover peptides able to distinguish different phenotypes.The peptide fingerprint was obtained by matrix-assisted laser desorption/ionization coupled to time-of-flight mass spectrometry. After statistical analysis, a subset of 45 ionic species was found differently expressed in the 4 groups considered, 12 of them peculiar to patients with FAP. Moreover, 4 ionic species were found significantly changed in the switch between adenoma and malignant carcinoma.Potentially prognostic peptides identified by this study derive mainly from circulating proteins, some of which are involved in the inflammatory response, such as complement C3 and C4 subjected to an exoprotease activity that seemed pathology related.In this study, we defined for the first time a specific panel of peptides for monitoring patients with FAP that could be profitably used to monitor and predict the pathologic evolution in adenocarcinoma malignancy.We use the mass spectrometry technique for the detection of circulating peptides in patients with familial adenomatous polyposis (FAP). We describe a FAP-specific fingerprint that allows early identification of the disease and neoplastic transformation. Our results are relevant because they could postpone preventive surgery as long as possible, improving the quality of life of patients with FAP.