Melphalan-prednisone (MP) has been the gold standard treatment for more than 30 years in elderly multiple myeloma (MM) patients. In order to assess whether the combination of dexamethasone with melphalan (MD) could improve on the efficacy of MP, we have carried out a randomized trial comparing both treatment approaches. A total of 201 patients >/=70 years old were included in the study. The overall response rate was similar after six cycles (MP: 67.9%versus MD: 64.5%) and after 12 cycles (MP: 49.4%versus MD: 46.1%). However, the proportion of complete responses (CR) was higher in the MD arm, particularly after 12 cycles (MD: 22.4%versus MP: 9.1%; P < 0.05). There was no significant difference in event-free survival (MP: 15.9 months versus MD: 23.3 months). The median overall survival in both arms was almost identical (MP: 29.4 months versus MD: 27.2 months; P = 0.63). No significant differences in haematological toxicity were observed, but non-haematological toxicity was significantly higher in the MD arm. According to these results MP remains as the gold standard for treatment of MM and should be the reference for comparison of new therapeutic approaches involving novel agents.