Melanoma is a malignant tumor with a varied histologic appearance. Melanoma composed of spindle cells may include desmoplastic and neurotropic melanoma. The histologic diagnosis of desmoplastic and neurotropic melanoma can be difficult. Although S100 protein stains a majority of these melanomas, the staining may be weak or focal. HMB-45, a more specific marker of melanoma, is frequently negative in desmoplastic and neurotropic melanoma. In order to aid the identification of desmoplastic and neurotropic melanoma, we stained 13 spindle cell melanomas (5 neurotropic melanomas, 5 desmoplastic melanomas, 3 spindle cell melanomas without either desmoplasia or neurotropism) with p75 NGF-R and compared the staining results with S100 and HMB-45. p75 NGF-R is the low affinity nerve growth factor receptor reported to be present on the surface of neural-crest-derived cells. Conventional melanoma as well as neurotized nevi, neurofibroma, spindle squamous carcinoma, atypical fibroxanthoma, dermatofibroma and scars were also stained with p75 NGF-R. p75 NGF-R stained all of the desmoplastic and neurotropic melanomas tested. In each of these cases, negative HMB-45 staining of the spindle cells was seen. In many cases the number and intensity of the spindle cells staining with p75 NGF-R was greater than with S100. Neurofibroma, neurotized nevi and focal cells in round cell melanoma also were stained with p75 NGF-R. All the squamous cell carcinomas, atypical fibroxanthomas, dermatofibromas and scars were negative for p75 NGF-R. Based on our results, p75 NGF-R may be useful as an additional confirmatory antibody in a melanoma panel, especially in differentiating desmoplastic and neurotropic melanomas from non-neural-crest-derived spindle cell lesions. We feel it also can be helpful in better identifying margins of excision of these melanomas. p75 NGF-R, like S100 protein, will not differentiate desmoplastic and neurotropic melanomas from other neural-crest-derived lesions.