C57BL/6 mice with syngeneic B16-F10 melanomas were treated 7 days after tumor inoculation into the footpad with local hyperthermia (HT) of 43.5 degrees C for 90 min. A combination of local 30 Gy X-irradiation (XRT) given 2, 4 or 12 h after HT cured the primary tumor in 34/35 mice, with irreversible damage to normal foot tissues in most of the animals. When 7.5, 10 or 15 Gy XRT were delivered 4, 18 or 24 h after HT, there were only a small number of cures and also a much smaller incidence of irreversible normal tissue damage. HT alone resulted in a significant (P less than 0.001) increase in metastases to regional lymph nodes (RLN) and the lungs. The 'curative' doses of combined XRT and HT resulted in a significant (P less than 0.001) decrease in metastasis to RLN and to the lungs. Conversely, subcurative doses of combined therapy resulted in an increase in RLN and lung metastasis (P less than 0.001). Abdominal lymph node metastasis, not usually seen in control mice, is markedly increased after HT alone or in combination with subcurative XRT (P less than 0.001). The overall survival of mice treated with HT alone is decreased (P less than 0.0028). The survival of mice treated with HT followed 4, 18 or 24 h later with 10 Gy XRT is further decreased (P less than 0.0025). These data show that subcurative HT, or XRT plus HT, increases the incidence of spontaneous metastasis in this syngeneic mouse melanoma model. Curative doses prevent this effect on metastasis, but there is an unacceptable incidence of irreversible damage to the tumor-bearing foot. The cause(s) of this phenomenon are not known.