The effect of fractionated radiation and hyperthermia was experimentally studied in a C3H mammary carcinoma and its surrounding skin. Simultaneous radiation and heat (42.5 C -6 0 minutes) with one or five fractions gave thermal enhancement ratios (TER) of approximately 2.5 in both tumor and surrounding skin, and no improved therapeutic effect was obtained. Five fractions of sequential treatment with heating four hours after radiation reduced the tumor TER to about 1.4, but when 72 hours were allowed between the fractions, no thermal enhancement of the skin was observed. Thus, an improved therapeutic ratio was observed. Clinically, the combined treatment was studied in 12 patients with 49 metastases from malignant melanoma treated with different schedules of radiation and hyperthermia (approximately 43 C for 30 minutes). Simultaneous treatment with three fractions in eight days gave TER values in the skin between 1.2-1.4, but a similar effect was found in the tumor. Three fractions of sequential treatment in eight days did not produce any thermal enhancement of the skin response, but still presented an apparent gain of the tumor response, and so seemed to increase the therapeutic effect. Based on these findings, the strategy for further clinical use of combined hyperthermia and radiation is discussed.