Whether squamous cell carcinoma (SCC) and adenocarcinoma (ADC) of the esophagus differ in their natural history and treatment outcome remains controversial. The aim of the study was to identify the similarities and differences between SCC and ADC in terms of their clinical and histologic presentations and the oncologic results. Curative esophagectomy was attempted in 742 consecutive patients between January 1982 and January 2002. Neoadjuvant radiochemotherapy was proposed for patients with locally advanced tumors. Demographic parameters, histomorphologic tumor characteristics, treatment strategies, postoperative mortality and morbidity rates, recurrence, and long-term prognosis were recorded retrospectively. The SCC and ADC groups were composed of 624 and 118 patients, respectively. ADC occurrence increased significantly during the study period. Compared to the SCC group, patients in the ADC group were significantly older and had a lower incidence of respiratory and otolaryngologic histories; they also had more advanced tumors and a higher percentage of invaded lymph nodes, shorter time until resumption of feeding, shorter hospital stay, a higher diffuse recurrence rate, and a lower incidence of tobacco-related second primary tumors. Five-year survival rates after R0 resection were 46% and 45% in the SCC and ADC groups, respectively (p = 0.804). There was a significant survival advantage for ADC patients with pT1, pN0, or stage I tumors (p < 0.050) and different independent prognostic factors than those with SCCs. In conclusion, the clinical, histologic, and oncologic differences between SCC and ADC justify a differentiated therapeutic concept for these two tumor entities and distinct consideration in clinical reports.