The bcl-2 gene is an oncogene that inhibits programmed cell death (apoptosis). We investigated by immunocytochemistry bcl-2 expression in normal colonic mucosa, hyperplastic polyps, adenomas, and adenocarcinomas of the large bowel. The purpose of the investigation was twofold; to assess the possible role of bcl-2 in colorectal tumorigenesis and to evaluate its clinical significance. The cases studied included 24 hyperplastic polyps, 49 adenomas, and 205 colorectal carcinomas. In both normal mucosa and hyperplastic polyps bcl-2 immunoreactivity was detected only in the proliferative cells of the colonic crypts. Conversely, bcl-2 immunoreactivity was noted in all adenomas irrespective of the degree of dysplastic change; it was diffuse in 84% of adenomas and focal in the remaining cases. In colorectal carcinomas bcl-2 expression was undetectable in 50% and focal (less than 50% immunostained neoplastic cells) in 38% of tumors. The remaining 12% of the carcinomas displayed diffuse (more than 50% immunostained neoplastic cells) bcl-2 immunoreactivity. In colorectal carcinomas bcl-2 expression was not correlated with relevant clinicopathologic parameters, including disease stage, tumor location and growth fraction, DNA ploidy, and p53 protein accumulation, and had no prognostic significance by univariate or multivariate analysis. These results suggest that bcl-2 oncoprotein may play a role in colorectal tumorigenesis, probably in the early phases of the adenoma-carcinoma sequence. bcl-2 expression in established tumors has no prognostic significance.