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Introduction: The inducible Cyclooxygenase (COX)-2 enzyme plays an important role in inflammation and carcinogenesis. Recent reports suggest that single nucleotide polymorphisms (SNPs) in the COX-2 gene may alter enzyme function and in turn modify an individual's risk of colon cancer. We explored the association between the COX-2 Val511Ala SNP and risk of colon cancer among 240 African American cases and 326 African American controls in a population-based, case-control study in North Carolina., Methods: We used unconditional logistic regression models to determine the odds ratios (ORs) for genotype and risk of colon cancer., Results: We observed a non-statistically significant inverse association between any Ala COX-2 genotype and risk of colon cancer (OR = 0.62, 95% CI: 0.33, 1.16) among African Americans. The inverse association was present among non-regular NSAID users, use < or = 3 times/week, (OR = 0.66; 95% CI: 0.32, 1.37) and regular NSAID users, use > or =3 times/week for > or =3 months, (OR = 0.41; 95% CI: 0.11, 1.54)., Conclusions: Our results suggest that the COX-2 Val511Ala SNP does not antagonize the effect of NSAIDs on colon cancer risk and provides support that NSAID use and the COX-2 Val511Ala SNP may contribute to a reduced risk of colon cancer among African Americans.