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Hyperhomocysteinemia, a well-recognized cardiovascular risk factor, is frequent in hemodialysis (HD) patients. A common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C→T substitution at nucleotide 677, is associated with homocysteine (Hcy) level elevation. We examined whether three factors involved in the methionine cycle could influence plasma Hcy concentrations in HD patients: MTHFR polymorphism; vitamin B12, an essential cofactor; and folate, the substrate. In a cross-sectional study, serum vitamin B12, folate, and plasma Hcy were measured and MTHFR genotyping was performed in 534 HD patients. Effects of MTHFR genotypes, vitamin B12, and folate on plasma Hcy levels were examined in 450 HD patients not administered vitamin B12or folate. To examine the effect of vitamin B12on plasma Hcy concentrations, we compared plasma Hcy concentrations in HD patients with and without vitamin B12supplementation. To examine whether functional vitamin B12deficiency exists even in HD patients with normal vitamin B12concentrations, 15 HD patients (serum vitamin B12concentrations, 250 to 2,100 pg/mL) were treated with vitamin B12(mecobalamin, 1.5 mg/d) for 8 weeks. Serum concentrations of methylmalonic acid (MMA) and vitamin B12were measured. Hcy levels were higher and folate levels were lower in patients with the TT and CT genotypes compared with patients with the CC genotype. Analysis of covariance to determine independent predictors of high Hcy levels identified low serum vitamin B12and folate levels and high albumin (Alb) levels in CC-genotype patients, low folate levels and high Alb levels in CT-genotype patients, and low folate levels in TT-genotype patients. Plasma Hcy levels were lower in CC- and CT-genotype patients with vitamin B12supplementation than in those without supplementation. Vitamin B12supplementation for 8 weeks significantly reduced MMA concentrations in HD patients with normal serum vitamin B12concentrations. These results indicate that MTHFR genotype influences the correlation of Hcy level with vitamin B12and folate levels in HD patients. Functional vitamin B12deficiency may exist, even in HD patients with normal vitamin B12concentrations. The efficacy of vitamin B12and folate supplementation on plasma Hcy levels may depend on MTHFR genotype. © 2002 by the National Kidney Foundation, Inc.