Of a total of 928 primary esophageal cancers, 16 cases of "undifferentiated" esophageal carcinoma were isolated. The topographic and age distributions as well as the clinical presentation and evolution of these tumors were basically similar to those of the usual esophageal squamous carcinoma. By light microscopy, the tumors were comprised exclusively or predominantly of small, round-to-fusiform cells. The cytoplasm appeared scanty and the nuclei were comparatively large and hyperchromatic. Mitotic activity was prominent. Four of the sixteen neoplasms showed occasional foci of squamous differentiation. Argyrophilic cells were seen in all cases, although their number and distribution were variable. Occasional mucosubstance droplets were present in 2 cases. Argentaffin and amyloid stains were negative in all tumors. Ultrastructural studies revealed variable numbers of granules consisting of a dense core, a pale halo, and a single, delimiting membrane; these measured between 80 and 220 nm in diameter. Four of the sixteen cases displayed conspicuous tonofilament bundles and rare keratohyalin granules. The predominant ultrastructural common denominator of these tumors was the presence of characteristic neurosecretory-type granules; thus, their classification as neuroendocrine carcinomas would appear justified. Nevertheless, the abundant tonofilaments and the rare keratohyalin granules and mucosubstance droplets seen in several cases indicate that some of these epithelial cancers possess and express variable capabilities toward multidirectional differentiation.