E-cadherin is among tumor suppressor genes which mostly subjects to the down-regulation in squamous cell carcinoma of esophagus (SCCE). The gene is tightly associated with the tumor invasion and metastasis in multiple human cancers, especially SCCE. CpG islands’ methylation in the promoter region of E-cadherin is among the mechanisms that have been suggested for the E-cadherin silencing, however, little is known regarding (SCCE) in the high risk region of the world. To establish a correlation between E-Cadherin promoter methylation with the pathological features of SCCE, as well as history, and demographic features we undertook the present investigation. Following to the surgical resection tissue samples of the 44 patients with SCCE was used for E-cadherin promoter methylation examination. Analysis was done using methylation specific polymerase chain reaction (MS-PCR). Furthermore, for evaluating E-daherin expression levels, reverse transcription PCR (RT-PCR) was applied.Results have indicated that twenty four out of the forty four tumor DNA samples (54.5%) were aberrantly methylated. In contrast, all normal tissues were found to be unmethylated. In addition a significant association was found between methylation status of E-Cadherin promoter with type I and II of the tumor differentiation (p=0.024), stages T2 and T3 of tumors (p= 0.026), as well as lymph node invasion (p= 0.004). E-cadherin tumor suppressor gene subjects to epigenetic silencing through aberrant promoter CpG islands methylation; a mechanism which is most commonly contributed with the other important tumor suppressor genes in the SCCE carcinogenesis in the world’s highest risk region for SCCE.