High-dose melphalan and auto-SCT (HDM/SCT) induces hematological complete responses (HCRs) in 40% of patients with immunoglobulin light chain (AL) amyloidosis. However, relapses occur in 8% of patients who initially achieve HCR. We conducted a study to explore the feasibility and efficacy of a second HDM/SCT in this setting. Eleven patients were enrolled. Five patients underwent repeat stem cell mobilization with G-CSF; the others had stem cells cryopreserved from the first mobilization. Six patients received 200 mg/m(2) HDM; five patients received modified HDM at 140 mg/m(2). Engraftment occurred at a median of 10 days for neutrophils and 12 days for platelets. There was no treatment-related mortality or death within the first year, but significant grade III/IV non-hematological toxicities occurred. In all, 4 of 11 patients (36%) achieved HCR at 1 year. Two of these patients are in continuous remission at 3 and 6 years; the other two relapsed at 2 and 3 years. Of the four patients who achieved partial hematological response at 1 year, three have relapsed at a median of 3 years. Three patients died of progressive disease at 1-2 years. In conclusion, one-third of patients with AL amyloidosis who relapse after HDM/SCT can achieve HCR with a second SCT.