Schwann cell differentiation has been proposed in the histogenesis of neurotropic melanoma by light and electron microscopic studies, and melanosomes are rarely, if ever, detected in the spindle cell component of this tumor. S-100 immunoreactivity has previously been demonstrated in Schwann cells of benign neurogenic tumors and most malignant melanomas. The authors report S-100 immunoreactivity in spindle cell elements of neurotropic melanoma. Focal neuron-specific enolase immunoreactivity was also found. These findings, in the absence of melanosomes in tumor cells, support the contention that the spindle cell element of neurotropic melanoma is derived from cells of neural crest origin.