Myelin oligodendrocyte glycoprotein (MOG) is postulated to be a target autoantigen in multiple sclerosis (MS). Here we investigated the encephalitogenicity of an immunodominant epitope of MOG, peptide 35-55, in various strains of mice. An MS-like disease was induced in NOD/Lt mice (H-2g7) and C57BL/6 mice (H-2b) by a single injection of MOG35-55 in CFA. The disease followed a relapsing-remitting course in NOD/Lt mice, whereas C57BL/6 mice developed a chronic paralytic disease. Histologically, the disease in both strains was characterized by cellular infiltration and multifocal demyelination in the CNS. Significant DTH type reactions to MOG35-55 were only seen in MOG-susceptible animals, with the NOD/Lt mice showing the strongest responses. Susceptible mice also showed specific antibody responses to MOG35-55 but not to a panel of other MOG peptides. These results provide further evidence for the role of MOG as a highly autoantigenic molecule capable of inducing severe demyelinating disease.