Previous segregation analyses of pedigrees from areas of China where esophageal squamous cell carcinoma (ESCC) rates are extraordinarily high suggested a Mendelian mode of transmission. We initiated a search for a major ESCC gene by conducting a genome-wide scan in ESCC tumors. Chromosome 13 showed loss of heterozygosity (LOH) in 95% of microsatellite markers, the highest frequency of LOH on any chromosome. In the current study, we established a high-resolution deletion map using 107 markers on 13q and compared LOH frequency by family history of upper gastrointestinal cancer. Overall allelic loss was significantly higher in those with a positive (versus negative) family history, suggesting the presence of an inherited tumor suppressor gene on 13q in ESCC.