Purpose: As a pre-malignant precursor, adenoma provides an ideal tissue for proteome profiling to investigate early colorectal cancer development and provide possible targets for preventive interventions. The aim of this study was to identify patterns of differential protein expression that distinguish colorectal adenoma from normal tissue. Experimental design: Twenty paired samples of adenoma and normal mucosa were analysed by 2-DE and MALDI-TOF/TOF MS to detect proteins with ≥2-fold differential expression. Results: Four proteins were up-regulated in adenoma (Annexin A3, S100A11, S100P and eIF5A-1) and three were down-regulated (Galectin-1, S100A9 and FABPL). S100P, galectin-1, S100A9 and FABPL expression was localised by immunohistochemistry. Conclusions and clinical relevance: Distinctive patterns of in vivo protein expression in colorectal adenoma were identified for the first time. These proteins have important functions in cell differentiation, proliferation and metabolism, and may play a crucial role in early colorectal carcinogenesis. The ability to recognise premalignant lesions may have important applications in cancer prevention.