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Eighty-one patients treated with high-dose therapy and autologous stem cell transplantation (ASCT) as part of salvage therapy after a frontline ASCT were included in a retrospective analysis. The median time between the first and the salvage ASCT was 47 months. After salvage ASCT, 75 patients (93%) achieved at least a partial response, including 67% very good partial responses, and no toxic death was reported. Sixteen patients (20%) underwent consolidation therapy, whereas 30 patients (37%) underwent some form of maintenance therapy after salvage ASCT. For all patients, the median overall survival (OS) was 10 years from diagnosis and 4 years from salvage ASCT. The median progression-free survival (PFS) from the date of the first ASCT to the date of the first relapse was 40 months, and the median PFS from the date of salvage ASCT to the date of subsequent progression was 18 months. In the multivariate analysis of prognostic factors, three independent factors unfavorably affected PFS: a short duration of response to the first ASCT (cut-off value of 24 months), a response less than a very good partial response after salvage therapy, and no maintenance treatment after salvage ASCT. Age over 60 years and a short duration of response after the first ASCT were the two factors adversely affecting OS from the time of diagnosis and OS from the time of salvage ASCT. Our data show that salvage ASCT is a feasible option that should be routinely considered at the time of relapse for patients with a response duration of more than 2 years to frontline high-dose therapy.