Neurofibromas are often clinically, as well as histologically, indistinguishable from completely neurotized melanocytic nevi. We tested the hypothesis that immunologic markers would differentiate the perineural fibroblasts and Schwann cells of neurofibromas from the neurotized cells of melanocytic origin. We examined eight partially neurotized acquired melanocytic nevi, three partially neurotized congenital melanocytic nevi, and five neurofibromas, with antibodies directed against S-100 protein, Leu-7(HNK-1), glial fibrillary acid protein (GFAP), and myelin-basic protein (MBP). A histologic diagnosis of neurofibroma was based on identification of a dermal proliferation of spindle-shaped cells with wavy nuclei, in a background of loose reticulated collagen. Neurotized nevi were diagnosed upon recognition of scattered nests of type A or B nevus cells, surrounded by basement membrane, present in the papillary dermis of lesions otherwise indistinguishable from neurofibromas. The congenital nevi were all large melanocytic nevi known to be present at birth. S-100 stained the majority of neoplastic cells in all neurofibromas, neurotized acquired nevi, and neurotized congenital nevi. Neurofibromas showed focal staining for Leu-7, GFAP, and MBP. In contrast, neurotized acquired and congenital nevi failed to express these markers. We believe that Leu-7, GFAP, and MBP may be helpful in differentiating neurofibromas from completely neurotized melanocytic nevi. The differences in the immunohistochemical profiles of neurofibromas and neurotized nevi support the concept that these neoplasms are histogenically distinct, despite their similar histologic appearance.