The aim of the study was to evaluate the feasibility and the efficacy of high-dose chemoradiotherapy followed by autologous hematopoietic stem cell support with peripheral blood progenitor cells (PBPC) harvested after high-dose cyclophosphamide (HDCYC) treatment in patients with high-risk multiple myeloma (MM). Inclusion criteria were: age less than 65 years and high-risk MM defined as stage II MM, stage III MM, refractory or relapsed MM. The design of the study was: 1) HDCYC +/- hematopoietic growth factors followed by PBPC collection, and 2) high-dose melphalan combined with total body irradiation (or busulfan for previously irradiated patients) followed by PBPC reinfusion (ABPCT). All 60 patients completed the procedure except two who died from infection after HDCYC and another of acute cardiac failure after reinfusion of PBPC. Out of the 60 evaluable patients, three failed to respond while the other 57 achieved either a partial (n = 33) or complete (n = 24) response. Thirty-one patients progressed or relapsed after a median duration of response of 15 months (range: 3-43). The median follow-up for the other 26 responder patients was 24 months (range: 2-66). Twenty-one patients died, 18 of MM (2 after failure, 16 after relapse) and three responders of lung cancer (n = 1) and infection (n = 2). In conclusion, this study shows that this therapeutic approach is feasible and efficient.