Allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning was evaluated in 22 patients (median age 53, range 36-66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)-identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA-mismatched unrelated donor]. Graft-versus-host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant-related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2-19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8-36 months) post allografting. Estimated 2 year overall and event-free survival was, respectively, 25.5% and 22.0% for the whole patient group, and 62.5% and 57.1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0.0182) and absence of cGVHD (P = 0.069) were associated with shorter event-free survival. Thus long-term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.