Intracerebral infection with the DA strain of Theiler's murine encephalomyelitis virus induces a chronic demyelinating disease in SJL/J mice. Intraperitoneal inoculation with either the wild-type DA virus or an attenuated variant virus of DA, H7A6-2, results in protection from development of chronic demyelinating disease. Protective anti-viral immune responses result in reduced viral titers and decreased inflammation in the central nervous system within the first week following intracerebral challenge with virus. Development of protective immunity requires the presence of B cells and CD4+ T cells but does not require CD8+ T cells. High titers of serum anti-viral IgG and neutralizing antibodies are induced following the intraperitoneal inoculation with the DA virus or H7A6-2 virus prior to challenge. While protection could not be transferred with immune serum from DA virus-infected mice or neutralizing monoclonal antibodies, protection was correlated with increased numbers of DA virus-specific plasma cells in the central nervous system within the first week following intracerebral challenge. Protected mice also had enhanced levels of anti-DA virus IgG and neutralizing antibodies in the cerebral spinal fluid by 1 week following intracerebral challenge with DA virus. Thus, we conclude that vaccination with live virus results in protection from chronic demyelinating disease by inducing immune responses which are manifested in the central nervous system and rapidly clear infection after intracerebral challenge with DA virus.