The molecular pathogenesis of multiple sclerosis (MS) has not been fully defined although T cell-mediated immune destruction of myelin is thought to be an important component. Despite some benefits of immune modulating or suppressive agents such as prednisone, cyclophosphamide, or B interferon, no standard therapy is curative. Beginning in the 1960's, human bone marrow transplantation (BMT) was successfully performed to provide immune deficient patients (e.g., Severe Combined Immunodeficiency and Wiskott Aldrich Syndrome) with a functional immune system. In simplistic terms, treatment of MS by means of BMT is designed to ablate an aberrant immune system and then, similar to the use of marrow transplants for immunodeficient patients, reconstitute a new immune system in the hopes of re-establishing tolerance to the relevant autoepitopes during thymic development of the donor T cells. This hypothesis is supported by animal experiments. In specific, Experimental Allergic Encephalomylitis (EAE) is an animal model for multiple sclerosis. Immune ablation and syngeneic marrow rescue in animals with EAE can prevent or ameliorate clinical symptoms and eliminate the effector lymphocytes responsible for EAE from the central nervous system. We propose to test the efficacy of complete immune ablation followed by hematopoietic stem cell support in patients with malignant MS.