BUF rats suffering from severe relapsing experimental autoimmune encephalomyelitis (R-EAE), a model for multiple sclerosis, were treated with intensive cytoreductive therapy and grafting of allogeneic bone marrow (BM). BN.1B rats were used as EAE-resistant, largely MHC-matched donors, resembling human BMT from HLA-identical siblings. The treatment induces complete remission and low recurrence rates of R-EAE. Evidence is provided that the efficacy of the treatment depends on a high degree of lymphoablation: a minority of rats had host-type residual activated T lymphocytes in the CNS after treatment. Furthermore, complete replacement of host-type BM by donor-type hemopoietic cells is essential, as higher relapse rates were observed in animals with incomplete reconstitution by donor cells than in completely reconstituted rats. Overall, our results indicate that patients with severe MS might benefit from treatment with HLA-matched allogeneic BM.