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Millimeter wave irradiation has been found to generate a dose-dependent heating of skin, providing an opportunity for destruction of heat-sensitive cutaneous tumors including melanomas. In vitro irradiation of epidermal keratinocytes and melanoma cells revealed distinct susceptibility of melanoma cells to MMW hyperthermia with higher thermotolerance of keratinocytes. No significant species differences were found when human and murine keratinocytes and melanoma cells were compared. In vivo irradiation of cutaneous melanoma in mice with MMW at the incident power density of 1.25 W/cm2 for 30 min resulted in a selective melanoma destruction. Histological analysis showed no tissue damage of normal skin cells (necrosis or apoptosis) within the exposed skin areas. We hypothesize that MMW irradiation would be a useful treatment modality for cutaneous melanoma in humans.