Esophageal squamous cell carcinoma (ESCC), the predominant form of esophageal cancer in India, is an aggressive cancer associated with high mortality. In contrast, esophageal, adenocarcinoma (EA) is more common in the West. Our analyses revealed crucial molecular differences between ESCC and EA that were replicated in adenosquamous mixed tumor samples, perhaps indicating independent origin of the two components. We further profiled genome-wide DNA copy number and transcript profile in ESCC and results revealed interesting molecular features with respect to P53 status.