The association of A3, B7 and Dw2 histocompatibility (HLA) markers with multiple sclerosis (MS) is well established among North Europeans and Whites in the United States, but is apparently not universal. We previously showed that the incidence of A3, B7 and Dw2 was not higher among Israelis with MS. An association of A3 and B7 was also lacking in Italian, Jordanian and Japanese groups with MS. Recently, the HLA-DR antigen DR2 was shown to have a stronger association with MS than do A3 and B7. Conceivably, DR2 could be associated with MS even in populations where an association with A3 or B7 is lacking. Therefore, a study of DR antigens was carried out in 45 carefully defined Israeli MS patients and in matched control subjects. No significant association between MS and DR antigens was found. We conclude that the association between HLA antigens and MS is specific only to certain populations or particular regions. The implications of this observation on the role played by HLA antigens in the etiopathogenesis of MS is discussed.