Updated project metadata. Fecal immunochemical tests (FIT) detecting hemoglobin in stool are widely used for non-invasive colorectal cancer (CRC) screening, but their sensitivity leaves room for improvement. Our aim is to identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRCs and advanced adenomas (AAs). Stool samples (one series of 12 CRCs and 10 controls, and a second series of 81 CRCs, 40 AAs, 43 non-advanced adenomas and 129 controls) were analyzed by mass-spectrometry and searched for human proteins. Classification and regression tree and logistic regression analyses were performed to identify protein combinations that differentiated CRCs and/or AAs from controls. Antibody-based assays for four selected proteins were performed on an independent series of FIT samples (14 CRCs, 16 AAs, 18 non-advanced adenomas and 24 controls) Results: In total, 834 human proteins were identified, of which 29 were significantly enriched in CRCs versus controls in both stool sample series. Combinations of four proteins reached sensitivities of 80% and 45% for detecting CRCs and AAs, at 95% specificity, which was higher than hemoglobin alone.