Forty children with multiply relapsed cancers received iv melphalan at three doses: 30 mg/m2, 45 mg/m2, and 60 mg/m2. The hematologic toxicity was severe and protracted at all dose levels, whether or not the bone marrow was involved with tumor. Of 39 evaluable patients, 37 had grade 3 or 4 hematologic toxicity. Nonhematologic toxic effects were infrequent and not severe. Two complete responses (Hodgkin's disease, rhabdomyosarcoma), eight partial responses, and 30 failures were seen. There appeared to be a very narrow margin between efficacy and toxicity. Further study of melphalan in pediatric tumors may be warranted in special circumstances: in higher doses (greater than 100 mg/m2) as cytoreduction therapy for specific cancers with marrow rescue, or as part of combination therapy in certain cancers (eg, lymphoma, sarcoma), possibly at doses of 20 to 30 mg/m2 every 4 weeks.