The interaction between hyperthermia and cis-diamminedichloroplatinum(II) (c-DDP) given in various schedules as an adjuvant to radiation treatment was investigated in a C3H mouse mammary carcinoma in vivo. Both hyperthermia (43.5 degrees C for 60 min) and c-DDP (6 mg/kg i.p.) caused a delay in tumor growth when given individually. When c-DDP was given 4 h prior to hyperthermia, the increase in tumor growth time corresponded to an additive effect, but when the interval was reduced to 15 min, the tumor growth delay was significantly greater than additive. The modifying effect of these schedules on radiation was studied using local tumor control (50% tumor control dose) as the endpoint. c-DDP alone did not result in any enhancement of tumor control, irrespective of whether it was given 15 min or 4 h after irradiation. In contrast, heat treatment at 43.5 degrees C for 60 min given 4 h after irradiation resulted in a significant reduction in the 50% tumor control dose, with an enhancement ratio of 1.8. From a clamped local tumor control assay, it was found that c-DDP selectively killed aerobic cells, whereas hyperthermia was primarily directed toward the hypoxic clonogenic cells in the tumors. Combining the two modalities (simultaneously) resulted in a significant additional increase in the killing of well-oxygenated clonogenic cells, but the destruction of hypoxic cells was not different from that obtained after heat alone.