Background:Gastric Cancer (GC)as the third most common malignancy in Iran, accounts for ~50% of all GI cancers who cause 55% of all cancer-related deaths in Iran. Upper gastrointestinal cancer accounts for more than 50% of all cancer deaths in this area. Methylenetetrahydrofolatereductase (MTHFR) enzyme reductase catalyzes the conversion of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteineremethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, and some types of cancer, and mutations in this gene are associated with methylenetetrahydrofolatereductase deficiency. Individual with two copies of 677C (677CC) have the "normal" or "wildtype" genotype. Individuals of 677TT are predisposed to mild hyperhomocysteinemia, because they have less active MTHFR available to produce 5-methyltetrahydrofolate (which is used to decrease homocysteine). We aimed to study the association between this polymorphism and GC in our province.Methods: We enrolled 100 patients with mean age 65.9 Yrs. affected with primary GC and same age- and sex- matched healthy control participants. The analysis has been carried out by PCR-RFLP on DNA extractions from peripheral blood.Results: In the case group, the genotype was 45%, 515%, and 4% for CC, CT, and TT, respectively. And for controls were 62%, 33%, and 5%. In comparing case and control group, a significant association was found (P=0.006).Conclusion: Because of high frequency of GC in our province, the investigations about the role of genetic susceptibilities for GC are very important. Finding relationships could help us to find prognostic factors for persons who are at the risk of affecting to GC in.