X/Gf mice bearing the MT2 mammary adenocarcinoma were subjected to 4,000 rad of X rays given either as a single dose, or five daily fractions of 800 rad. Additional experimental groups were treated with either short term localized microwave hyperthermia (LMH) (42.5 degrees C for 25 min.), or the hypoxic cell radiosensitizer misonidazole (MISO) (0.67 mg/g bw), or both hyperthermia plus MISO with X rays. The combined use of MISO plus 42.5 degrees C with X rays was superior to the other treatment regimens as assessed by tumor regrowth delay and mean survival time. However, for the five fraction schedule, the addition of MISO plus hyperthermia was not as effective as observed for the single dose treatment. This may be attributed to reoxygenation of the hypoxic tumor cells between treatment fractions. MISO retention in tumor tissue under ambient and hyperthermic conditions was studied. The application of heat locally to the tumors caused a significant increase in MISO tumor concentration. However, after four X ray fractions the influence on MISO concentration by hyperthermia in the tumors could not be demonstrated. This may be related to the stromal damage by X rays in the tumor tissue that was observed histologically.