Backgroud: DNA methylaiton is an important mechanism for gene silence. The purpose of this study was to investigate aberrant promoter methylation of the p16 and FHIT genes in and tissues and plasma loss of protein expression in esophageal precancerous conditions (EPC) and esophageal squamous cell carcinoma (ESCC) of high-risk area. Methods: Methylation-specific PCR (MSP) was employed to examine the DNA methylation in the plasma and tissues of total 95 patients of EPC, ESCC and 10 chronic esophagitis (CE).Loss of protein expression of pl6 and FHIT was detected immunohistochemically. Results: In total 95 lesion tissues of EPC and ESCC, p16 methylation was found in 53 (55.79％) cases, and 41 of 53 (77.36％) cases were demonstrated deletion of the p16 protein immunohistochemically. FHIT methylation was found in 49 (51.58％) cases, and 40 of 49 (81.63％) were demonstrated deletion of the FHIT protein. Only 1 (10％) case of 10 CE was found p16 methylation in the tissues. In the plasma of total 105 samples, 2 of 23 high grade intraepithelial neoplasia (HGIN) and 12 of 37 ESCC were detected p16 methylaiton, and 2 of 23 HGIN and 14 of 37 ESCC were detected FHIT methylaiton. Conclusions: These results indicate that p16 and FHIT methylaion may be one of the earliest events and an important mechanism for gene silencing in esophageal squamous cell carcinogenesis. This study may be helpful for screening the candidate molecular markers for early diagnosis of ESCC in high-risk area.