Background: It has been reported that COX-2 expression is associated with MMP-2 expression in thyroid and breast cancers, suggesting that MMPs are linked to COX-2-mediated carcinogenesis. Several polymorphisms within the MMP2 promoter region have been reported in cases with oncogenesis and tumor progression, especially in colorectal carcinogenesis. Materials and Methods: This research evaluated risk of association of the SNPs, including genes for COX-2 (AIG transition at +202) and MMP-2 (Crr transition at-1306), with colorectal cancer in 125 patients and 125 healthy controls. Results and Conclusions: Our data confirmed that MMP2 C-1306 T mutations were significantly more common in colon cancer patients than in our control Saudi population; p=O.0121. On the other hand in our study, there was no significant association between genotype distribution ofthe COX2 polymorphism and colorectal cancer; p=0.847. An elevated frequency ofthe mutated genotype in the control group as compared to the patients subjects indeed suggested that this polymorphism could decrease risk in the Saudi population. Our study confirmed that the polymorphisms that could affect the expressions of MMP-2 and COX-2 the colon cancer patients were significantly higher than that in the COX-2 negative group. The frequency of individuals with MMP2 polymorphisms in colon cancer patients was higher than individuals with combination of COX2 and MMP2 polymorphisms. Our study confirmed that individuals who carried the polymorphisms that could affect the expressions ofCOX2 are more susceptible to colon cancer. MMP2 regulatory polymorphisms could be considered as protective; further studies need to confirm the results with more samples and healthy subjects.