AIM: To investigate the aberrant methylation of CHFR promoter in human gastric cancer (GC) and its impact on the expression of CHFR mRNA and protein, as well as its correlation with clinical and histological features of human GC.METHODS: Methylation-specific polymerase chain reaction (MSPCR) was used to detect the methylation status of CHFR promoter in 20 primary GC samples and paired normal gastric mucosa. The CHFR mRNA and protein expressions were investigated beth by RT-PCR and by Western blotting. The CHFR protein expression in 39 GC samples was immunohistochemicaliy examined.RESULTS: The DNA methylation of the CHFR gene was found in 9 of the 20 GC samples (45%) and the down-regulation of CHFR mRNA and protein was significantly associated with the methylation status of the CHFR gene (P = 0.006). In 20 samples of corresponding non-neoplastic mucosa, no DNA methylation of the CHFR gene was detected. The CHFR gene methylation in poorly differentiated GC samples was significantly higher than that in well-differentiated GC samples (P = 0.014). Moreover, the negative CHFR protein expression rate in paraffin-embedded GC samples was 55.07% (38/69), the positive rate in poorly differentiated GC samples was 36.73% (18/49),which was significantly lower than 65.00% (13/20) in well-differentiated GC samples (χ2 = 4.586, P = 0.032).CONCLUSION: Aberrant methylation of the CHFR gene may be involved in the carcinogenesis and development of GC, and is the predominant cause of down-regulation or loss of CHFR mRNA or protein expression. As aberrant methylation of CHFR promoter is correlated with tumor differentiation, it may help to predict the prognosis of GC and CHFR may become a novel target of gene therapy for GC in the future.