We report on two cases of central nervous system (CNS) relapse after high-dose chemotherapy and autologous stem cell transplantation. A 55-year-old man received two courses of vincristin, doxorubicin and dexamethasone (VAD) as an induction treatment for stage IIIB IgG kappa multiple myeloma. Bone marrow stem cell collection was performed after a high-dose melphalan (HDM) course (140 mg/m2). Autologous bone marrow transplantation (ABMT) was performed with this cryo-preserved unpurged bone marrow sample after a second HDM course. Three months after ABMT, the patient presented with signs of central nervous involvement with plasma cells and monoclonal IgG kappa in the cerebral fluid. The patient died despite systemic and intrathecal chemotherapy. A 50-year-old man was initially treated with 3 courses of VAD for a stage IIIA IgD lambda multiple myeloma. Blood stem cell were collected after a course of high-dose etoposide and cyclophosphamide. ABMT was performed after total body irradiation (TBI) and HDM. Three months later, he presented with right leg palsy and a lumbar puncture showed numerous plasma cells and the presence of the IgG lambda. The patient died of neurological complications three months later. Extramedullary occurred prior to medullary relapse in the two cases, suggesting the presence of an extramedullary clone of plasma cells with a high degree of chemo-resistance. Although high-dose chemotherapy appears promising, this therapeutic approach could allow the occurrence of presently unobserved complications. Wether CNS prophylaxis is indicated in this context, as recommended in leukemia, remains an open question.