Esophageal cancer is a frequently fatal malignancy, and is described in certain regions in Northeast India with an incidence of esophageal squamous cell carcinoma many fold higher than the rest of the population. The population in Northeast India is at higher risk due to poor nutritional status, consumption of fermented betel quid and other oral tobacco products besides smoking and alcohol intake. Cytokeratins (CKs) are the major constituents of the esophageal epithelium and may show gain or loss of CKs as the cancer progresses from normal epithelium to invasive phenotype. In this study, we studied the immunohistochemical expression of 5 CKs (CK4, CK5, CK8, CK14, and CK17) in the normal esophageal epithelium and esophageal squamous cell carcinoma from both the general population and the high-risk population of Assam in Northeast India. The CK expression profile was similar to other published data in general. Further analysis demonstrated differences in CK expression between the general and the high-risk tumor samples. CK5 and CK8 expression was altered in the high-risk population. The significance of these differences is unclear, but suggests a connection to the etiologic factors.