Following observation of the predictive value of the histologic extent of tumor cell destruction after preoperative chemotherapy for metastasis-free survival (MFS) in osteosarcoma, a randomized study was undertaken with the aim of (1) sparing some patients the unpleasant side effects of highly toxic drugs like doxorubicin (DOX) and cisplatin (CPDD) by administering these drugs postoperatively only after poor response with a milder preoperative regimen, and (2) improving the prognosis of patients responding poorly to the initial treatment by use of a salvage chemotherapy postoperatively. The available patients were divided into two groups. Those in the study arm received a preoperative chemotherapy consisting of high-dose methotrexate (HDMTX) and the triple drug combination of bleomycin, cyclophosphamide, and dactinomycin (BCD) and were switched to DOX/CPDD postoperatively in case of poor response. DOX/CPDD was used besides HDMTX for initial treatment in the control arm, and BCD alternatively with CPDD/ifosfamide (IFO) for postoperative salvage treatment. The response rate of the study arm was significantly inferior to the control arm (26% v 60%; P less than .001). The actuarial 4-year MFS rate of poor responders after salvage chemotherapy also was poorest in the study arm (41%); it was unchanged in the control arm (53%) as compared with that of poor responders from the COSS-80 study without salvage chemotherapy (52%). The actuarial 4-year MFS rate of good responders was 73% in the study arm, 79% in the control arm, and not significantly different from that of the COSS-80 study (84%), although postoperative chemotherapy of good responders had been markedly shortened as compared with the COSS-80 study. The actuarial 4-year MFS rate of the study arm as a whole was inferior to that of the control arm (49% v 68%; P less than .1) and also inferior to the COSS-80 study (68%; P less than .01), indicating a failure of the employed salvage strategy in general and especially of the effort to restrict the use of the very effective but highly toxic drugs DOX and CPDD to patients resistant to a less toxic initial treatment.