Increasing epidemiological studies have revealed the important role of methylenetetrahydrofolate reductase (MTHFR) in carcinogenesis. The association of MTHFR A1298C and MTHFR C677T polymorphisms with the risk for gastric cancer remains obscure due to inconsistent findings in independent studies among diverse ethnicities. A meta-analysis based on all available publications on this genetic association was performed. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to estimate the effect of MTHFR variants on gastric carcinogenesis. Totally, 25 eligible case-control studies were included into the meta-analysis according to the inclusion criteria. The MTHFR C677T polymorphism was demonstrated to significantly increase the susceptibility to gastric cancer (OR(T vs. C) = 1.21, 95% CI 1.10-1.34; OR(TT vs. CC )= 1.47, 95% CI 1.22-1.76; OR(TC vs. CC )= 1.20, 95% CI 1.03-1.40; OR(TT + TC vs. CC) = 1.27, 95% CI 1.10-1.47; OR(TT vs. CC + TC )= 1.29, 95% CI 1.15-1.46), whereas no significant correlation was observed when assessing the MTHFR A1298C polymorphism (OR(C vs. A )= 1.00, 95% CI 0.90-1.10; OR(CC vs. AA) = 0.99, 95% CI 0.75-1.31; OR(CA vs. AA )= 1.01, 95% CI 0.89-1.14; OR(CC + CA vs. AA) = 1.00, 95% CI 0.89-1.13; OR(CC vs. AA + CA) = 0.97, 95% CI 0.74-1.27). Subgroup analyses by ethnicity and source of controls further confirmed the findings in overall analysis. The meta-analysis suggests that the polymorphism of MTHFR C677T but not MTHFR A1298C confers a risk effect on the development of gastric cancer among Asians and Caucasians, which provides a new insight into the gastric cancer pathogenesis.