Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism. This study with381 esophageal cancer patients and 432 healthy controls was conducted to examine the association of MTHFRC677T and A1298C polymorphisms with susceptibility to esophageal cancer (EC) in a Chinese population.Compared with the CC genotype of MTHFR C677T, subjects carrying homozygote TT and variant genotypes(CT+TT) demonstrated reduced risk of EC with adjusted ORs (95% CI) of 0.44 (0.28-0.71) and 0.57 (0.37-0.88),respectively. However, no association was found between the MTHFR A1298C polymorphism and the risk ofEC. Comparing to haplotype CA, haplotypes TA and TC could reduce the susceptibility to EC with adjustedORs (95% CI) of 0.61(0.47-0.79) and 0.06 (0.01-0.43), respectively. In conclusion, the present study suggestedthat the MTHFR C677T polymorphism can markedly influence the risk of EC in Chinese.