Based on our prior experience in treating children with metastatic osteogenic sarcoma, a multidrug regimen was developed. Nine children with evaluable osteogenic sarcoma were treated with vincristine 1.5 mg/m2 on day 1, highdose methotrexate 200-300 mg/kg i.v. on day 2, with p.o. citrovorum factor "rescue" 9 mg every 6 hours x 12, followed in 2 weeks by cyclophosphamide 40 mg/kg i.v., then 2 weeks later Adriamycin 1.5 mg/kg/day x 2; in 2 weeks cyclophosphamide was repeated. After a 2-week rest, the 56-day cycle was repeated for a total period of 1 year. Oropharyngeal mucositis was the most frequent severe manifestation of gastrointestinal toxicity. Hematologic depression was mild to severe. Nine patients with clinically evaluable osteogenic sarcoma and no previous chemotherapeutic treatment were treated with this regimen. One patient had only a transient shrinkage in tumor mass, and one patient had no progression of multiple pulmonary and bone metastases for 16 months while on therapy. Of the remaining seven patients, all had clinically significant responses with tumor regression demonstrated for from 5 to 20+ months. Four of these patients (three presenting with primary tumor and pulmonary metastases) demonstrated regression of their primary tumor. In an attempt to increase the cure rate in osteogenic sarcoma, chemotherapy that has proven to be effective against metastatic osteogenic sarcoma should now be employed as prophylactic therapy, after amputation, at cancer treatment centers where it can be safely and effectively administered.