Bone marrow transplantation (BMT) potentially represents a novel therapy for the amelioration and even cure for multiple sclerosis (MS). It has important advantages over immunosuppressive drug treatments because, while effecting broad-based ablation of the immune system and autoreactive cells, it provides an important means for overcoming the resultant immunodeficiency, while possibly restoring self-tolerance. However, both of these benefits are predicated on a functional thymus that undergoes profound age-induced atrophy from puberty. Reversal of thymic atrophy has been achieved by several procedures, including removal of sex steroids by surgical or chemical (LHRH agonist) castration. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we combined BMT with androgen depletion to induce immune regeneration, and investigated the kinetics of increased thymic function on immune reconstitution and disease reduction. We show that androgen depletion significantly increased the efficacy of BMT to ameliorate the clinical signs of EAE while concurrently restoring the periphery with increased naive and regulatory lymphocytic populations. Upon rechallenge, mice with a regenerated thymus had a slower onset of clinical symptoms compared with mice undergoing BMT only. These results suggest that thymic regeneration strategies may be used as a complement to conventional BMT protocols for the treatment of MS.