This study aims to elucidate the incidence and the therapeutic and prognostic implications of co-existent non-esophageal primary malignant neoplasms in patients with esophageal cancer. Between 1974 and 1997, 33 patients with esophageal cancer treated at the Nippon Medical School Hospital were documented as having multiple primary malignant neoplasms (MPN). The therapeutic strategies and post-therapeutic survival of these patients were retrospectively investigated. Among 291 patients with esophageal cancer, 33 patients (11.3%) were also found to have non-esophageal primary malignant neoplasms. Twenty patients (60.6%) had synchronous MPN and 13 (39.4%) had metachronous MPN. Among the MPN, apart from esophageal cancer, gastric (32.6%) and head and neck cancer (32.6%) were the most common. The incidence of esophageal cancer occuring in association with cancers of the head and neck or gastric cancer was high. Frequent examination in these cancer patients, using fiberoptic esophagogastric endoscopy for example, may be helpful in the early diagnosis of esophageal cancer.