This study compared retrospectively the effectiveness, toxicity and hematopoietic recovery after autologous peripheral blood stem cell transplantation (ASCT) of two consecutive peripheral blood stem cell mobilization regimens in newly diagnosed MM patients. Patients in group 1 (n = 178) were treated with 4 g/m2 of cyclophosphamide (CY) plus G-CSF (5 μg/kg/day). Patients in group 2 (n = 117) with 750 mg/m2 of VP16 plus G-CSF (10 μg/kg/day). Optimal mobilization, defined by a target number of 8 × 106 CD34+ cells/kg collected, was achieved in 62.4% and 89.7% of patients in groups 1 and 2, respectively (P < 10-4). The median number of aphaeresis sessions was reduced from two in group 1 to one in group 2 (P < 10-4). Grade4 neutropenia, febrile neutropenia and IV antibiotic use were significantly more frequent in group 1 than in group 2 (P < 10-4). Red blood cell transfusion requirements were significantly greater in group 1 (P = 0.007). The switch to VP16-G-CSF10 resulted in a significant reduction of the number of hospitalization days (P < 10-4). Neutrophil and platelet recovery after ASCT occurred on days 11 and 12, respectively, in the two groups with no significant differences. VP16+G-CSF10 allowed liberation of resources in the clinical and aphaeresis departments and demonstrated a better effectiveness-safety profile than CY+G-CSF5.