Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking are environmental risk factors for ESCC, whereas single nucleotide polymorphisms in ADH1B and ALDH2, which increase harmful intermediates produced by drinking, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in in Japan to determine the mutational landscape of this cancer.