While photodynamic therapy (PDT) for cutaneous malignancies including dermal recurrences of breast cancer and basal cell carcinomas has shown great promise, PDT of malignant melanoma has remained incompletely understood. A comparison study of the effects of PDT on human xenograft amelanotic and melanotic malignant melanoma in the athymic nude mouse model was performed. Twenty-four hours after ip administration of Photofrin II, the responses to total laser light doses of 25-300 J/cm2 were evaluated by histologic examination. Animals were also sacrificed 24 hours after administration of Photofrin II without light, and their uptake and localization of hematoporphyrin derivative (HpD) for each tumor were measured and compared. The results indicate that human xenograft melanotic melanoma, despite the fact that it contains more HpD than does amelanotic melanoma, is far less responsive to PDT. This result appears to be due to the competing chromophore melanin, which may inhibit the photochemical reaction at several key points.