Abstract: Peutz-Jegher Syndrome (PJS) is an autosomal dominant inherited disease, characterized by gastrointestinal (GI) hamartomatous polyps frequently associated with GI and non-GI tumors, leading to reassessment of cancer risk in this lesion. Another type of hamartomatous polyps, the hyperplastic polyps, is common in the colon and in its pure form carries no risk of malignancy, whereas adenomas of the colon are considered premalignant. There is an increasing interest in a “hamartoma-adenoma-carcinoma sequence” to explain the development of colon cancer in PJS patients. This can occur through disturbance in cell proliferation, apoptosis and/or the loss of contact inhibition. Design: Eighteen Peutz Jegher colonic polyps, 20 hyperplastic polyps and 23 adenomas were immunohistochemically stained to detect bcl-2, bax, p53, Ki-67 and b-catenin. Computerized image analysis of each stain was performed to detect: Labeling index (LI), Mean optical density (MOD), Quick score (QS) and Concentration heterogeneity (CH). Results: Ki-67 LI was higher in adenomas than in Peutz Jegher polyps (PJP) and in PJP than in hyperplastic polyps. Bcl-2 LI was higher in adenomas and in PJP than in hyperplastic polyps. P53 was higher in adenomas than in PJP and hyperplastic polyps. Bax was higher in PJP and in hyperplastic polyps compared to adenomas. B-catenin staining was strictly confined to the basolateral border in hyperplastic polyps, similar to its distribution in normal mucosa. Whereas adenomas exhibited cytoplasmic staining, with focal nuclear stain in 43.5% of cases, PJP displayed weak cytoplasmic stain in 22.2% of the polyps examined but only one case showed nuclear stain (5.6%). Conclusion: High expression of bcl-2 in colorectal adenomas suggests that it is important in early phases of cell transformation to malignant phenotype. Hyperplastic polyps’ low expression of bcl-2 reactivity suggests that these lesions, unlike adenomas, have low malignant potential. As bcl-2 LI in PJP was higher compared to hyperplastic polyps, bcl-2 appears to be the earliest gene playing a role in the “hamartoma-adenoma-carcinoma” sequence. Bax LI is higher in hyperplastic polyps and PJP compared to adenomas, suggesting decreased bax expression in  “hamartoma-adenoma-carcinoma” sequence. P53 mutation has no apparent role in hamartoma-adenoma sequence. Relocalization of b-catenin from the membrane to the cytoplasm and/or the nucleus may be a good indicator of progression of hamartoma to a true neoplasm