Mucoepidermoid carcinoma of the esophagus (MEC) is uncommon and has not been fully investigated. The biological behavior and clinical aspects of MEC were studied. The clinical features of eight patients with MEC were compared with 51 cases of squamous cell carcinoma of the esophagus (SCC). Proliferating cell nuclear antigen (PCNA), p53, and carcinoembryonic antigen (CEA) were stained in the resected specimens by immunohistochemistry. Seven out of 8 cases (87.5%) had stage III by TNM classification. Four cases died of widespread metastases and 2 cases died of local recurrence within 2 years after the surgery. Neither chemotherapy and radiotherapy were effective against MEC. Overall median survival periods were 10.8 months for MEC and 32.1 months for SCC (P<0.05). When patients in stage III alone were compared, MEC tended to have a worse prognosis than SCC (P=0.058). Immunohistochemical studies revealed that the positive rates of PCNA and CEA were significantly higher in MEC than in SCC (P<0.05), while there was no significant difference in p53 positive rate. Esophageal MEC had an aggressive biological nature and was resistant to adjuvant therapies. The poor prognosis of esophageal MEC may be caused by high proliferative and metastatic potential.