The aim of the study was to evaluate the expression of tumor suppressor genes p53, fragile histidine triad gene (FHIT), and an oncogene insulin-like growth factor 2 (IGF2) as prognostic markers in the etiology of esophageal cancer. Immunohistochemistry (IHC) was performed in 39 archival tissue samples of different esophageal pathologies for the three genes. Abnormal p53 expression was maximum in all the cases of squamous cell carcinoma, while IGF2 expression was enhanced in squamous cell carcinoma (81%), adenocarcinoma (100%), and dysplasia of squamous epithelium (75%) samples when compared with normals (50%). To our surprise, 75% of normal tissues did not show FHIT expression, which was also not seen in 40% of dysplasias of squamous epithelium, 33.3% of adenocarcinoma, and 41% of squamous cell carcinoma. To the best of our knowledge, this is the first study evaluating IGF2 by IHC, as well as, correlating it with the expression of the two tumor suppressor genes, p53 and FHIT, in esophageal tissue. p53 expression was threefold higher than normal in dysplasias of squamous epithelium and adenocarcinoma, while it was eightfold higher in squamous cell carcinoma. IGF2 expression was low in normal and dysplasia tissue but was increased 1.97-fold in both types of malignancy. FHIT and p53 expression were well correlated in squamous cell carcinoma, supporting the observation that FHIT regulates and stabilizes p53. Altered/lowered FHIT levels may be a result of exposure to various exogenous agents; however, this could not be assessed in the present study as it was carried out on archival samples. A larger prospective study is warranted to establish the role of exogenous factors in FHIT expression.