The presence and distribution of cytokeratins, actin, neurofilament protein, neuron-specific enolase, S-100 protein, and different neuropeptides were studied immunohistochemically by the peroxidase-antiperoxidase immunoenzyme method or the avidin-biotin-peroxidase technique in 10 patients with primary cutaneous neuroendocrine carcinoma. In all cases of cutaneous neuroendocrine carcinoma, immunoreactivity for neuronspecific enolase, cytokeratin, and neurofilament was identified. No staining was found after incubation with antibodies to S-100 protein, actin, and other tested neuropeptides. The cytoplasmic cytokeratin and neurofila-ment immunoreactivity was particularly strong in perinuclear areas, sometimes showing an annular pattern or displaying a discoid profile.The diagnosis of cutaneous neuroendocrine carcinoma may be reliably made by the immunocytochemical demonstration of neuron-specific enolase and intermediate filaments (cytokeratin, neurofilament protein) by conventional microscopy. Cutaneous neuroendocrine carcinoma has morphological, immunological, and histogenetic similarities to carcinoid neoplasms of the gut. We favor the concept that cutaneous neuroendocrine carcinoma is derived from, or differentiates toward, dermal neuroendocrine cells.