Immunization with myelin basic protein (MBP) in complete Freund's adjuvant failed to induce experimental allergic encephalomyelitis (EAE) in six resistant mouse strains studied: A/J, BALB/c C3H/HeJ, AKR, NZW and DBA/2. However, treatment of challenged mice with anti-interferon-gamma (IFN-gamma) monoclonal antibody (mAb) induced severe EAE in mice of all strains except AKR. Furthermore, anti-IFN-gamma mAb treatment led to increased disease incidence and severity in BALB/c mice challenged with the MBP peptide87-103, known to be encephalitogenic for the susceptible SJL strain. In three strains tested, anti-IFN-gamma mAb enhanced passively induced EAE in the A/J and C3H/HeJ but not in the BALB/c mice. All mice with clinically overt EAE had widespread histological lesions characterized by mononuclear cell infiltrates and focal demyelination. The results indicate that resistant strains are genetically capable of developing EAE, and that IFN-gamma can contribute to disease resistance.