Abstract: Among three epigenetic mechanisms, DNA methylation is a distinct and crucial mechanism to regulate a variety of genes in tissue specific manner in pathophysiology of cancer. Methylation status of four selected genes which include tumor suppressor genes like p53 and FHIT as well as oncogenes, Aurora-A and IGF2 was assessed to find the association with esophageal cancer by performing methylation specific restriction assay in both blood and tissue of patients who had undergone diagnostic endoscopy and results were correlated with the exogenous factors like tobacco, alcohol, hot beverages and diet. Individuals with all four types of exposure were found in a higher percentage in the cancer group when compared to normals and esophagitis, however, those exposed to tobacco and alcohol were significantly more in cancer (p<0.05). The methylation status of p53, FHIT and IGF2 did not show difference between cancer and normal samples whereas Aurora (p = 0.0002). But methylation was increased in p53, FHIT and Aurora-A gene and decreased in IGF2 in cancer tissue if the individuals were exposed to tobacco and alcohol. MDR analysis indicated that the four genes evaluated were acting independently whereas there was a stronger interaction between non vegetarian diet and hot beverages as well as tobacco and alcohol for the development of esophageal cancer. In conclusion it can be stated that exogenous factors affect the methylation status of genes in tissues which may act as an early step in esophageal carcinogenesis.