The causal link between therapeutic irradiation and malignant melanoma has not been firmly established. The authors report a novel case of a malignant melanoma arising from a therapeutically irradiated neovagina reconstructed from skin flaps following radical vulvectomy with inguinal lymph node dissection 16 years earlier. The diagnosis was established by light microscopy and immunohistochemical staining. Reports of melanoma arising from sites of previous radiation therapy are reviewed. Our observations suggest that therapeutic radiation may be a factor in the development of malignant melanoma, particularly in non-sun-exposed areas, including the genital tract.