The mitochondrial DNA 4977-bp deletion (Delta upmtDNA4977) has been explored in various cancers, but its predictive or prognostic role in esophageal cancer is poorly understood. The objective of the present study was to investigate a possible role of Delta upmtDNA4977 in susceptibility and prognosis of esophageal cancer in a northern Indian population. The study was performed in 39 histopathologically confirmed cases with esophageal cancer. Tumor, normal tissues, and intravenous blood samples were taken for detection of Delta upmtDNA4977 through a duplex polymerase chain reaction technique. Delta upmtDNA4977 was detected in two tumors and one adjacent normal tissue sample, but in none of the blood samples. All three patients with Delta upmtDNA4977 were male, with squamous cell carcinoma in the middle third of the esophagus. Survival analysis suggested a role of Delta upmtDNA4977 in prognosis of esophageal cancer patients. Despite the low frequency of Delta upmtDNA4977 in esophageal cancer patients of northern India, this feature may have a role in esophageal cancer progression and prediction of survival outcome.