The susceptibility to multiple sclerosis (MS), a chronic neurological autoimmune disease that primarily targets CNS myelin, has long been associated with HLA class-II genes. Although several other HLA and non-HLA disease predisposing alleles have been identified, alleles of the HLA-DR15 haplotype (DRB1*1501, DRB5*0101, and DQB1*0602) remain the strongest susceptibility factor. Many studies have suggested that the HLA-DRB1*1501 allele determines MS-associated susceptibility. However, due to strong linkage disequilibrium within the HLA class II region, it has been difficult to unequivocally determine the relative roles of the DRB1*1501 and DQB1*0602 products. In this study we use HLA class-II transgenic mice to illuminate the relative contributions of the DRB1*1501 and DQB1*0602 alleles or their combination to susceptibility toward a new "humanized" MS-like disease induced by myelin-associated oligodendrocytic basic protein (MOBP). Although many immunological studies have focused overwhelmingly on the role of the HLA-DRB1*1501 product in MS, we show that HLA-DRB1*1501 transgenics are refractory to MOBP disease induction, whereas the HLA-DQB1*0602 transgenics are susceptible via T cells reactive against MOBP15-36 and MOBP55-77 encephalitogenic epitopes. Although both transgenics react against these epitopes, the MOBP15-36- and MOBP55-77-reactive T cells are of Th2-type in HLA-DRB1*1501 transgenics and are pathogenic Th1/Th17 cells in the HLA-DQB1*0602 transgenic mice. This new humanized model of MS further implicates autoimmunity against MOBP in MS pathogenesis, provides the first evidence of pathogenic HLA-DQ-associated anti-myelin autoimmunity, and is the first to offer a rationale for HLA-DQB1*0602 association with MS. These findings have important bearing on the candidacy of the DQB1*0602 allele as a genetic risk factor for MS.