Esophageal cancer (EC) is one of the six most common cancers across the world. The striking 3-4: 1male predominance of esophageal squamous cell carcinoma (ESCC) has not yet been well explained. Our hypothesis is that the changes in level of estrogen and/or subtype of estrogen receptor (ER) may exert a protective factor in esophageal carcinogenesis and thus estrogen analogues may represent a promising target for prevention and treatment of ESCC. Several lines of evidence in a mouse ESCC model have suggested an inhibitory role of estrogen in ESCC growth and development. Consistent with this, our results showed that male and female counterparts from a high incidence area (HIA) for EC had significantly decreased serum estradiol compared to healthy controls from a low incidence area (LIA). Moreover, serum level of estradiol of ESCC patients from the HIA were significantly lower compared to healthy controls from both HIA and LIA. Numerous studies indicate that relatively low androgen level, high estrogen level (environmental and endogenous) and ratio alteration of sex hormones are important factors explaining decreased ESCC incidence. Both ERalpha and ERbeta are ligands to estradiol with different effects on transcription at activator protein-1 sites. Estrogen exerts a suppressive effect, mainly through ERalpha in ESCC, and an accelerative function, mainly through ERbeta. Our hypothesis suggests that administration of novel potent estrogen analogues might be an effective measure for prevention and treatment of ESCC in HIA.