We report a case of radiation-induced mucosal melanoma in a 41-year-old woman with a history of childhood rhabdomyosarcoma of the nasal cavity that had been treated with radiotherapy. During the workup for the melanoma, the patient was found to be negative for S-100 protein on immunostaining. While many melanotic markers for the histologic confirmation of melanoma exist, they can be negative in some cases, such as ours. To the best of our knowledge, only 1 case of radiation-induced melanoma has been previously reported in the English-language literature, and in that case the patient was S-100-positive. Although our case is rare, it suggests another possible long-term adverse effect of radiotherapy. We also describe the morphologies and histology associated with diagnosing melanoma in an S-100-negative patient.