Introduction: Conditioning regimen with oral busulfan (BU) and melphalan (MEL) for patients with multiple myeloma (MM) undergoing autologous transplant (ASCT) has been associated with a high incidence of liver complications, especially severe sinusoidal occlusive syndrome (SOS).Material and methods: We conducted the current study to assess the toxicity profile and outcomes associated with ASCT after intravenous (iv) BU-based conditioning in 45 patients (24 M/21 F; median age 60 years, range 34–71) with MM. Front-line chemotherapy consisted of VBMCP/VBAD (31cases), VAD (8 cases), and other regimens (6 cases). At transplant, 8 patients were in complete response (2 with negative immunofixation) 24 in partial response, 13 with other responses (6 with minor response, 5 had progressive disease, 1 stable disease, and 1 patient no evaluated). Median interval from diagnosis to transplant was 11 months (range 5–80). Conditioning regimen consisted of iv BU (3.2 mg/kg in a single daily dose, days −5 to −3) and MEL (140 mg/m2, day −2). In 39 patients this was the first ASCT and the remaining 6 had relapsed after a previous ASCT conditioned with MEL-based regimens.Results: Median number of CD34+ cells administered was 2.9 x10^6/kg (range 1–5.8). Hematopoietic recovery was fast with median (range) time to 0.5 PMN and 20 platelets x10^9/L of 12 (11–46) and 13 (9–64) days, respectively. The toxicity profile was favourable. Particularly, no case of SOS, commonly seen with the oral BU, has been reported. Mucositis was the non-hematopoietic toxicity most frequently seen (42 cases). Other toxicities observed were uncommon (gastrointestinal toxicity, 6 cases, increase of liver enzymes, 3 cases and mild cardiac failure, 1 case). Fever was observed in 38 patients: fever of unknown origin in 21 cases, microbiologically documented infection in 13 cases and clinically documented infection in the remaining 4 cases. Only 2 patients (4%) died due to transplant-related toxicity (one patient to pneumonia, day 51; the other patient to sepsis to Acinetobacter baumani, day 54). With a median follow-up of 18 months, 41 patients had been evaluated for response: 19 are in complete response (9 with negative immunofixation), 16 in partial response, 2 with minor response, 2 had progressive disease, and 2 transplant-related deaths. The 18 months actuarial overall and progression-free survival rates are 95±3% and 70±10%, respectively. Interestingly, in 19 patients significant improvement response was observed after transplant.Conclusions: These preliminary results show that iv BU-containing regimen for MM is associated with an acceptable toxicity profile and with a high anti-myeloma effect.