Squamous cell carcinoma of the esophagus has an uneven geographic distribution with a strong prevalence in the South Carolina Lowcountry. Although many environmental influences and some genetic factors have been implicated in its development, the molecular events required for tumorigenesis have not been defined. Point mutations in the p53 tumor suppressor gene are the most commonly noted genetic defect in human tumors. Our study shows that p53 point mutations occur more frequently in patients with esophageal cancer from this region than in patients from other areas of the world where the disease is prevalent.