Forty-three patients with osteosarcoma were treated with amputation and adjuvant chemotherapy utilizing a four-drug combination of cyclophosphamide, vincristine, phenylalanine mustard, and adriamycin (CONPADRI-I regimen). Twenty-four patients (56 per cent) remained free of metastases twelve to sixty-one months after diagnosis. Ten of the twenty-four have been disease-free for more than three years. Another group of thirty patients was treated with amputation and a five-drug adjuvant chemotherapy program which included the administration of massive doses of methotrexate with citrovorum factor (COMPADRI-II regimen). Twenty of the thirty (67 per cent) remained free of metastases from twelve to twenty-six months after amputation (median, sixteen months). Two deaths related to methotrexate toxicity occurred. Late metastases developed in three patients (at sixteen, nineteen, and twenty-six months after operation) in the group treated with the COMPADRI-II regimen.