Neurofibromas and schwannomas express S100 protein, while axon filaments are not commonly found in schwannomas. Histopathological distinction between neurofibromas and schwannomas is usually easy, except for some variants. To assess the reliability of immunohistochemistry results for the differential diagnosis of the latter, 46 neural tumors of the skin were studied: 31 schwannomas [12 schwannomatosis, 7 neurofibromatosis type 2 (NF2)-associated, 12 solitary] and 15 plexiform neurofibromas associated with neurofibromatosis type 1. All tumors were subjected to immunohistochemical-labeling studies with antibodies to S100 protein and axon-specific neurofilament proteins. All tumors were positive with anti-S100 protein antibody. Schwannomas were strongly and diffusely positive while neurofibromas displayed more varied and limited S100 protein reactivity. Axon filaments were detected in 15 of 15 plexiform neurofibromas and 7 of 19 schwannomas associated with NF2/schwannomatosis. None of the 12 solitary schwannomas reacted with anti-axon neurofilament antibodies. Aberrant axons were observed in the schwannomas associated with NF2/schwannomatosis but not in the solitary schwannomas. Therefore, when there are multiple neural tumors, immunohistochemical visualization of axons may be misleading if it is not related to the clinical context and the standard histological features.