It is known that cells in a nutritionally deprived and acidic environment are sensitive to heat. In general these same cells are chronically hypoxic and therefore heat possesses the potential to eliminate (some) of this radioresistant population. A direct radiosensitization is observed when heat is given simultaneously with radiation. This effect occurs to the same extent in both aerobic and hypoxic cells, thus the oxygen enhancement ratio is unchanged. By giving heat several hours after radiation the direct radiosensitization is avoided and the specific heat killing of the acidic, chronically hypoxic, tumor cells may be utilized to improve the therapeutic gain. The current investigation clearly demonstrates this concept in a C3H mammary carcinoma using a local tumor control assay. This effect could be further enhanced by adding hypoxic radiosensitizers (nimorazole, misonidazole) or a blood flow modifier (nicotinamide) which can eliminate acutely hypoxic cells.