Multiple sclerosis (MS) is shown to be associated with the HLA class II genes. The presence of strong linkage disequilibrium between HLA DR and DQ molecules in humans makes it difficult to identify the individual roles of HLA DR and HLA DQ molecule in MS pathogenesis. To address this problem, we used HLA class II transgenic mice and the experimental autoimmune encephalitis (EAE) model. Administration of recombinant MOG (rMOG) induced severe inflammation and demyelination in the central nervous system (CNS) of HLA DRB1*1502 mice (60%), whereas no disease was observed in HLA DQB1*0601(0%) and mild disease was observed in DQB1*0302 mice (13%). Lymphocyte proliferation was blocked by anti HLA antibodies, confirming that the rMOG was functionally presented by the HLA molecules. Introduction of DQB1*0302 into DRB1*1502 mice resulted in the development of chronic progressive clinical disease characterized by severe inflammation and demyelination (90%) in response to immunization with rMOG, whereas mild disease was observed when DQB1*0601 was introduced in DRB1*1502 mice (30%). This would suggest that the presence of more than one susceptible allele, namely HLA DRB1*1502 and DQB1*0302 resulted in enhanced severity of disease in the DRB1*1502/DQB1*0302 mice, possibly due to the additional selection and expansion of potential autoreactive T cells. The use of defined single and double HLA transgenic mice may reveal the intricate interactions between class II molecules in human disease.