234 patients with nonmetastatic osteosarcoma were randomized to preoperative chemotherapy of high-dose methotrexate with either doxorubicin or with etoposide and ifosfamide. After a median of 77-month follow-up, patients who had received the etoposide-ifosfamide regimen exhibited a larger percentage of good histologic response. Three- and 5-year overall and event-free survival rates were significantly better in those who had a good histologic response. Furthermore, although the event-free survival was slightly greater in the etoposide-ifosamide group compared to the doxorubicin group, this difference was not found to be statistically significant.