Seventy-six patients with classic high-grade osteosarcoma of an extremity received adjuvant chemotherapy by two protocols, initiated in 1972 and 1977, respectively, after appropriate amputations. Chemotherapy consisted of high-dose methotrexate, doxorubicin, and cyclophosphamide. Dose intensity of high-dose methotrexate and doxorubicin was greater for the patients treated with the protocol initiated in 1977. The proportion of long-term disease-free survivors on the two protocols are 46% and 56%. A better outcome (P = 0.042) was seen for the latter group, which received more intensive chemotherapy. Overall, metastases developed in 35 patients; in 19 who were receiving chemotherapy and in 16 after chemotherapy. The outcome for these two protocols, compared with two control groups that were given no chemotherapy or ineffective chemotherapy (biweekly vincristine and cyclophosphamide), confirms the results of controlled studies that showed an advantage of adjuvant chemotherapy after amputation for osteosarcoma.