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Backround and Objectives: Gene promoter hypermethylation is common in colorectal cancer and is associated with transcriptional silencing. However, the clinicopathological significance of p16INK4a gene silencing with hypermethylation is unknown. Therefore, the aim of this study was to analyze loss of p16 expression and its relationship to hypermethylation in sporadic colorectal cancer. Methods: Tissue from 426 colorectal cancers underwent histological analysis. Immunohistochemistry was performed for p16 expression. Fresh tumor DNA was analyzed for microsatellite instability (MSI) and the presence of K-ras mutations. In addition, DNA was bisulphite-modified and analyzed for p16INK4a promoter methylation by methylation-specific PCR. Results :There were 25% of tumors with p16INK4a promoter hypermethylation. These tumors were associated with older patients, right-sidedness, MSI and were poorly differentiated, mucinous, and had intraepithelial and peritumoral lymphocytes and a Crohn's-type lymphocytic reaction (P < 0.05). However, only right-sidedness was significant on multivariate analysis (P < 0.001). Only 8.1% of tumors did not express p16, and this was associated with hypermethylation (P < 0.05). Conclusion: p16INK4a promoter methylation, although common in colorectal cancer, does not result in a clinicopathologically distinct subgroup of tumors and infrequently results in transcriptional silencing. This suggests that p16INK4a gene inactivation does not have an important role in the pathogenesis of sporadic colorectal cancer.