The effect of treatments with the hypoxic cell radiosensitizers misonidazole (MISO), SR-2508, RSU-1069, and with the radioprotector WR-2721 on spontaneously disseminated Lewis lung carcinoma (LLC) and B16 melanoma (B16M) was investigated. Tumors were implanted into the tails of C57BL mice and were surgically removed after reaching volumes of approximately 40 mm3. This technique results in the induction of metastatic disease in lungs and at other anatomical sites and allows the independent treatment of disseminated tumor cells. The radiosensitizers and the radioprotector were administered 24 hr after surgery and animals were killed 14 and 30 days after removal of LLC and B16M, respectively. The time to death from spontaneous metastases was also measured. Both single treatments with large doses of MISO (1.0 g/kg) and fractionated therapy with smaller doses (0.5 g/kg on 5 consecutive days) promoted the formation of metastases to the lungs, lymph nodes and other organs. The survival times of MISO treated animals did not differ from control animals but manifestation of metastatic disease in the lungs and other organs occurred at earlier times. Administration of equitoxic doses of SR-2508 (3.0 g/kg) and RSU-1069 (0.1 g/kg) also promoted metastases formation. Mice treated with these radiosensitizers developed more metastases in the lungs and at other sites. Treatment with a single dose of WR-2721 (0.4 g/kg) promoted lung metastases but exerted a suppressive effect on lymph node tumors. When the radioprotector was given in fractionated schedules in three different doses (0.05 g/kg, 0.1 g/kg and 0.2 g/kg for 10 consecutive days) a slight enhancement of lung metastases and suppression of extrapulmonary metastases was observed.