Objective: Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects. Results: The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B12, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P < 0.001) in the homozygous variants (6.7 ± 0.6 ng/mL) compared with wild-types (8.8 ± 0.4 ng/mL) and heterozygotes (9.1 ± 0.5 ng/mL). Homocysteine was significantly higher (P < 0.05) in homozygous variants (13.2 ± 1.1 μmol/L) compared with homozygous subjects (10.9 ± 0.4 μmol/L). Homozygous variants had significantly lower (P < 0.05) RBC folate (84.7 ± 6.3 ng/mL) compared with wild-types (112.2 ± 5.2 ng/mL) and heterozygous individuals (125.1 ± 6.6 ng/mL). No significant difference in RBC folate was observed between wild-types and heterozygotes. The A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B12, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants. Conclusion: Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA.