Synchronous multiple primary malignancies are relatively unusual. We describe a case of synchronous triple cancers located at the middle and lower esophagus and the stomach in a 59-year-old Taiwanese man who presented with progressive dysphagia, epigastralgia, and bodyweight loss in 1 month. Endoscopic and histological features, microsatellite instability status of genomic DNA, and immunohistochemical staining of p53, MUC2, Fhit, c-erbB-2 and E-cadherin of all three cancers were demonstrated. We noted that these three cancers arose from different clones and that p53 mutation, instead of microsatellite instability, may play a major role in the development of multiple primary malignancies in this patient.