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A common polymorphism in a folate-metabolizing gene, methylenetetrahydrofolate reductase (MTHFR) 677C > T has been associated with reduced risk of colorectal cancer. In this study, we investigated whether a second common polymorphism of the gene, MTHFR 1298A > C, is an independent risk factor for colorectal cancer and if it is associated with plasma folate and total homocysteine (tHcy) levels. We also examined whether the 677C > T and 1298A > C polymorphisms are in linkage disequilibrium and whether combined heterozygosity confers additional (or reduced) risk of colorectal cancer. We conducted a nested case–control study of 211 incident colorectal cancer cases and 343 controls in the prospective Physicians’ Health Study. The MTHFR 677C > T and 1298A > C polymorphisms were in linkage disequilibrium in this population. Compared to MTHFR 1298AA genotype, multivariate-adjusted relative risk of colorectal cancer was 0.73 (95% CI 0.37–1.43) for the MTHFR 1298CC genotype. The slight reduction in risk was not a result of its linkage disequilibrium with the 677C > T polymorphism. This polymorphism was not significantly correlated with the plasma folate and tHcy levels. The combined heterozygosity did not modify the cancer risk; nor did it change the plasma folate and tHcy significantly. We conclude that the MTHFR 1298A > C polymorphism is a less substantial independent risk factor for colorectal cancer compared to the 677C > T polymorphism.