Primary high-grade neuroendocrine carcinoma of the esophagus (HNCE) is rare and poorly understood. In this study, we aimed at delineating the clinicopathologic and immunohistochemical characteristics of HNCE diagnosed on the basis of the World Health Organization criteria for pulmonary neuroendocrine carcinomas. We identified 42 (3.8%) consecutive resection cases of HNCE among 1105 esophageal cancers over a 7-year period. Patients' mean age was 62 years (range, 47 to 79 y) with a male to female ratio of 3.7. Dysphagia was present in 79% of patients and tobacco abuse in 50%. Most tumors were centered in the middle (52%) or lower (36%) esophagus; 48% were ulcerated and 31% exophytic. All tumors were sharply demarcated with a pushing border in either solid sheet (83%) or nodular (17%) growth patterns. Pure HNCE was found in 57%, and the remainder also exhibited small components of squamous cell carcinoma (SqCC) or glandular, signet ring cell differentiations. SqCC in situ was present in 50%. Most tumors (88%) were the small cell type with pure oat-like cells in 52%, and the larger spindled, anaplastic, and giant cells were common. Tumor crush artifact (98%) and the Azzopardi effect (88%) were widespread. Extensive lymphovascular (50%) and perineural (33%) invasion and metastasis to regional (48%) and abdominal celiac lymph nodes (29%) were observed. Neoplastic cells were immunoreactive to synaptophysin (100%), CD56 (93%), chromogranin A (67%), p63 (55%), TTF-1 (71%), CK8/18 (90%), CD117 (86%), HER2 (16%), and p16 (84%) antibodies. The 5-year survival rate was 25%, similar to that of SqCC. Lymphovascular and perineural invasion was associated with a worse prognosis.