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Globally, colorectal cancer is the third most commonly diagnosed cancer in males and the second in females, with 1.4 million new cases and almost 694,000 deaths estimated to have occurred in 2012. In colorectal carcinogenesis disturbances different from mutations called an epigenetic regulation are also taken into consideration. The epigenetic analysis revealed that P16 and mgmt promoter hypermethylation was significantly higher in cases compared to controls. Occurrence of P16 and MGMT promoter hypermethylation was found to be significantly more in males than in females. P16 and MGMT promoter hypermethylation was insignificantly found to be higher in Stage III/IV. Also, the degree of P16 and MGMT promoter hypermethylation increased significantly with the increasing severity. A significant correlation between P16 and MGMT promoter methylation and loss of expression of their corresponding proteins was observed. The Met/Met genotype of COMT gene was significantly associated with both P16 and MGMT promoter hypermethylation. This study demonstrated that P16 and MGMT promoter methylation is a frequent epigenetic event and may play an important role in the development of CRC.