Studies have suggested that low dietary folate intake is associated with an increased risk of gastric cancer. Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and influences DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. We hypothesized that three MTHFR common variants (i.e. C677T, A1298C and G1793A) and their haplotypes are associated with the risk of gastric cancer. To test this hypothesis, we genotyped these polymorphisms in a population-based case-control study of 320 incident gastric adenocarcinoma cases and 313 cancer-free controls in a Chinese population. Consistent with our previous observations, the 677TT genotype was associated with a significantly increased risk for gastric cancer (adjusted OR =1.79, 95% CI =1.02-3.15) compared with the 677CC genotype; the association was more evident for gastric cardia adenocarcinoma (adjusted OR =2.60, 95% CI =1.30-5.21). When we used the haplotype analyses and assumed MTHFR 677T, 1298C and 1793A as risk alleles, individuals with 6 variant alleles had a significantly (4.64-fold) increased risk for gastric cardia adenocarcinoma (OR =4.64, 95% CI =1.34-16.01) compared with those having 0-2 variants. These findings suggest that the MTHFR common variants and their haplotypes may play a role in the etiology of gastric cancer, particularly gastric cardia adenocarcinoma. Future studies using large sample sizes and incorporating detailed data on dietary folate intake and related serological measurements are warranted to confirm our findings.