For patients with relapsed or refractory multiple myeloma (MM) treated with a prior high-dose therapy (HDT) followed by autologous peripheral blood stem cell transplantation (PBSCT), the reapplication of HDT is a widely used salvage strategy. In this retrospective study, we report on 55 patients who were treated with salvage HDT at our institution. The conditioning regimen consisted of melphalan 200 mg/m(2) (27%), melphalan 140 mg/m(2) and busulfan 12 mg/kg body weight (40%), or melphalan 200 mg/m(2) and bortezomib 1.3 mg/m(2) (33%). Treatment-related mortality was 5% and response rates were as follows: 9% complete remission, 9% very good partial remission, 56% partial remission, 11% minimal response + stable disease, and 4% progressive disease (5% not assessable). Toxicity was moderate and the median event-free (EFS) and overall survival (OS) were 14 months and 52 months, respectively. The different conditioning regimens did not result in differences in terms of remission rates, EFS and OS, or toxicity. In multivariate analysis a duration of remission of more than 12 months after the first transplant was the only predictive factor for both EFS (p < 0.0001) and OS (p = 0.0001). In conclusion, salvage HDT followed by autologous PBSCT is an effective treatment option for patients with relapsed or refractory MM, while patients with an early relapse after their first transplant do not benefit from this treatment modality.