A radiation and chemotherapy-resistant murine osteosarcoma was used to investigate the possible effects of radiation and chemotherapy for the treatment of microscopic nests of tumor. Microfoci of tumor were simulated by injecting 1 x 106 cells subcutaneously (s.c.) and allowing the tumor to grow to an average size of ≃ 9.04 x 106 cells. Alkaline phosphatase was correlated to cell number as previously published for this model. Local irradiation of the site with 400-2400 R was ineffective. Cyclophosphamide at 200 mg/kg produced 30% cures and surgery gave 90% cures. Combination of irradiation and chemotherapy produced greater incidence of cures provided both modalities were used at the maximum dosages (cyclophosphamide at 200 mg/kg and irradiation at 2400 R). From these studies we conclude that radiation alone would be ineffective for treatment of microfoci of osteosarcoma cells that have metastasized to the lungs. Combination therapy using both modalities at maximum dosages may produce some longterm survivors, but the results are not promising. The effect of combination treatment on animals with large primary tumors 2 to 3 x 108 cells/mouse produce measurable tumor reductions but no cures. In combination with a low dose of drugs, CP50, a noticeable response due to radiation effects was measured only at 2400 R. At lower radiation, 400-1600R, no effect on the tumor was measured. With higher drug dose, CP200, 1600R produced measurable radiation effect on the tumor. No effect was seen at 400-800R. The best effect from radiation with CP was obtained when the drug was used at maximum tolerated dose.