We examined four melanotic neuroectodermal tumors (three jaw, one epididymis) of infancy (MNTI) by the immunoperoxidase method for intermediate filament-, neuroendocrine-, and melanoma-associated antigen profiles comparing these immunoreactions with those of 10 pediatric neuroblastomas, five retinoblastomas, and five retinas. Three MNTIs had larger pigmented epithelioid cells and small neuroblastic cells; one was composed mainly of pigmented epithelioid cells. One or more melanoma-associated antigens (HMB-45, HMB-50) and cytokeratin were consistently expressed in the large cells (four of four). The small cells stained for neuron-specific enolase (two of three) and synaptophysin (two of three). Neurofilament- and microtubular-associated proteins were demonstrated in the frozen tissue of one tumor. Both cell types were positive for vimentin, while negative for chromogranin A and S-100. Variable numbers of cells expressed desmin in one case, and muscle-specific actin in two cases. In contrast, neuroblastoma and retinoblastomas stained variably for vimentin, neuron-specific enolase, synaptophysin, and chromogranin. Neither tumor contained melanoma-associated antigens or cytokeratin. Pigment epithelium of the retina coexpressed cytokeratin and melanoma-associated antigens but lacked S-100. The results show that MNTI is a distinctive primitive neoplasm with a polyphenotypic profile of epithelial, neuroblastic, melanin-producing, and mesenchymal differentiation. Melanocytic differentiation in MNTI is distinguished from melanoma by lack of S-100 protein with consistent expression of cytokeratin. Myogenic differentiation in MNTI is a potential source of confusion with rhabdomyosarcomas, especially in small biopsy specimens. Coexpression of cytokeratin and melanoma-associated antigens by pigment-containing cells is similar to that of retinal pigment epithelium.