Methylenetetrahydrofolate reductase (MTHFR) plays a centralrole in converting folate to methyl donor for DNA methylation, an epigenetic modification known to be dysregulated in carcinogenesis. Our previous study revealed that MTHFR polymorphisms contribute to a great risk of esophageal cancer in a Chinese population. This case-control study was to examine the association between MTHFR polymorphisms and gastric cardia adenocarcinoma (GCA), which is also prevalent in high-risk areas of esophageal cancer and thus may share common etiological factors with esophageal cancer in this population. The study subjects were 217 patients with GCA and 468 population controls matched on sex and age. The MTHFR C677T and A1298C genotypes were detected by a PCR-based RFLP assay. It was found that subjects with the MTHFR 677TT variant genotype had a 2-fold increased risk of GCA (odds ratio, 2.04; 95% confidence interval, 1.28-3.26). Moreover, a significantly elevated risk was also seen among the MTHFR 677CT heterozygotes (odds ratio, 1.56; 95% confidence interval, 1.03-2.36). The MTHFR A1298C polymorphism had no effect on risk of GCA. These findings are generally consistent with our initial observation for esophageal cancer and suggest that the MTHFR genotype may be a determinant of GCA among this at-risk Chinese population.