The aim of the study was to determine the activity and toxicity of melphalan as a single agent given in up-front therapy for patients with newly-diagnosed Ewing's family tumours with bone/bone marrow metastases. Nineteen patients were enrolled from 2001 to 2004. The treatment consisted of up-front therapy with melphalan (two courses of 50 mg/m2, 3 weeks apart). The overall rate of response to melphalan (complete response+partial response, according to the RECIST criteria) was 78%. Transient grade 3-4 neutropenia, thrombocytopenia and anaemia were recorded in 97%, 81% and 28% of melphalan courses, respectively. No other relevant toxicities were recorded. Melphalan proved to be active in up-front treatment at non-myeloablative doses, and its toxicity was predictable and manageable. The schedule adopted did not interfere with any further intensive chemotherapy or myeloablative treatment in the majority of cases.