Methylene tetrahydrofolate reductase (MTHFR) is the key enzyme in folate metabolism. We examined whether single nucleotide 677 C-->T mutation in the MTHFR gene could affect the occurrence of skin lesions in endemic arsenic poisoning.Fifty individuals with arsenic-induced skin lesions were identified as cases, and 35 individuals without skin lesions from the same village were selected as controls. The MTHFR C677T polymorphism was analyzed by PCR-RFLP method, serum folic acid and Vitamin B12 were determined by microbiological assay and the electrochemiluminescence immunoassay, respectively.The frequencies of TT genotype and T allele in case group were 34.0% and 56.0%, respectively, and were not significantly different from those in controls. There was no significant difference between case and control group in the levels of folic acid and Vitamin B12 in serum. Compared to subjects carrying the CC genotype and having the level of folic acid above 10.5 nmol/L, other subjects were at elevated risk of skin lesions, but the 95% CI of both crude OR and adjusted OR (controlled for age, gender, smoking and arsenic level in drinking water) include 1.This study did not find the relationship between MTHFR gene (677C-->T) mutation and skin lesions in endemic arsenic poisoning.