OBJECTIVE To study the association between methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism and esophageal cancer risk. METHODS esophageal cancer cases, 150 esophageal precancerous lesions cases and 207 healthy controls were selected in a high esophageal cancer incidence region in Huai'an, China. MTHFR genotypes at the C677T site were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Chi-square test was used to estimate MTHFR genotype frequency distribution in the control, esophageal precancerous lesions (mild, moderate and severe) and esophageal cancer groups. RESULTS MTHFR C677T genotype distributions in the control and esophageal cancer groups had no significant differences. There was a significant difference in the frequency distribution of MTHFR 677TT genotype and T allele between the esophageal precancerous lesions group and the control group (P < 0.05). Compared with the mild group, the MTHFR 677TT genotype distribution in the moderate or severe esophageal precancerous lesions groups and T allele in the moderate group had significant differences (P < 0.05). CONCLUSIONS There may be no correlation between the MTHFR C677T gene polymorphism and susceptibility to esophageal cancer, but it had correlation with susceptibility to esophageal precancerous lesions. Individuals with MTHFR 677TT variant genotypes and T allele were at higher risk of esophageal precancerous lesions.