The response to hyperthermic treatment (42.5 degrees C for 60 min) of 5 human malignant melanomas grown in athymic mice (BALB/c/nu/nu/BOM) was studied. Local hyperthermia was given by immersing the tumor-bearing leg of the mice into a thermostatically regulated water bath. Growth delay studies indicated that the melanomas were different in heat responsiveness. The differences were confirmed by measuring the fraction of clonogenic cells in the melanomas as a function of time after treatment. The latter experiment showed that some tumor cells were inactivated during the treatment, while others lost clonogenicity first after completion of the treatment. Examinations of histological sections from tumors fixed 1 h after treatment revealed considerable vascular occlusion in all 5 melanomas. This indicates that the observed delayed cell death might be due to a number of factors, e.g., insufficient supply of oxygen and nutrients, increased tumor acidity, and accumulation of toxic metabolic products. It is concluded that at least two different mechanisms govern the overall heat response of the melanoma xenografts: the primary cell death, induced during treatment, is due to direct cytotoxic effects of the heat; the secondary cell death, induced after completion of treatment, is due to heat-induced vascular damage. The differences among the melanomas in overall heat responsiveness appeared mainly to be a consequence of differences in secondary cell death. The secondary cell death was shown to be least pronounced for those melanomas in which most of the larger vessels were embedded in broad bands of connective tissue.