Objective: The aim of this study was to evaluate whether p53 or bcl-2 protein expression in rectosigmoid adenomas is associated with histological characteristics of the adenomas and with presence of synchronous advanced proximal neoplasms. Methods: Seventy-six average-risk patients who underwent total colonoscopy and had rectosigmoid adenoma(s) were studied. An adenoma was considered advanced if villous histology and/or severe dysplasia and/or diameter >1 cm were present. p53 And bcl-2 protein expression was immunohistochemically examined using specific monoclonal antibodies. Results: p53 Protein was detected in 43% and bcl-2 in 93% of the 76 rectosigmoid adenomas. Advanced compared with nonadvanced adenomas were significantly more frequently p53-positive (28 of 44 or 63.6% vs five of 32 or 15.6%, p < 10 −4) or had a bcl-2 score of 12 (20 of 44 or 45.5% vs five of 32 or 15.6%, p = 0.007). Proximal advanced neoplasms were mainly found in patients with rectosigmoid adenomas positive for p53 and with a bcl-2 score of 12 (six of 17 or 35.3% vs 2/59 or 3.4%, OR: 15.6, p = 0.001) and in particular in those with advanced rectosigmoid adenomas positive for p53 and with a bcl-2 score of 12 (six of 13 or 46.2% vs two of 31 or 6.5%, OR: 12.4, p = 0.007). Conclusion: p53 Expression and bcl-2 protein overexpression in rectosigmoid adenomas are associated with advanced histology and a high risk of synchronous advanced proximal colon neoplasm.