This study investigated whether methylenetetrahydrofolate reductase MTHFR 677C>T polymorphism modified gastric cancer (GC) risk independently as well as in combination with folate intake and alcohol consumption. A hospital-based case-control study of 201 cases and 427 controls was conducted in three geographical areas of Mexico, between 1994 and 1996. The MTHFR 677T allele frequency was 51.0% in cases compared with 45.3% in controls. After controlling for dietary sources of folate, alcohol intake and other selected variables, a significant increase in GC risk was found among carriers of the 677TT genotype compared with those with the 677CC genotype (odds ratio (OR) 1.62, 95% confidence interval (CI) 1.00-2.59), with a significant trend (P = 0.048). There were no significant interactions between the MTHFR polymorphism and consumption of folate and alcohol. Our results suggest that the high prevalence of MTHFR 677T allele may be a contributor to the high rate of morbidity and mortality in GC in Mexico.