In the esophagus, alterations in the p53 tumor suppressor gene are associated with the development of preinvasive neoplastic lesions to invasive carcinoma. The role of p53 gene mutation in the progression of esophageal cancer still remains unclear. In this study, 82 DNA samples extracted from formalin-fixed, paraffin-embedded esophageal cancer tissues were analyzed for p53 mutation by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. All the patients had been treated surgically and were Japanese. Exons 5 through 8 of the p53 gene were amplified in DNAs and the mutations detected in 28 cases (34%) did not correlate with tumor location, histopathologic classification, histologic depth of tumor invasion, lymph node involvement or clinical stage. Among 39 patients with stage 3 and 4 disease who had undergone radical esophageal resection, those with p53 mutation had a poorer prognosis, the two-year survival being 25.4% compared with 61.2% for those without p53 mutation (P<0.01). These results suggest that p53 gene mutations play an important role not only in the genesis but also the progression of human esophageal cancer.