The frequency of HLA-DR2/DR4 heterozygotes was significantly higher in 85 Japanese patients with systemic lupus erythematosus (SLE), compared with healthy controls. There was no difference in frequency of the heterozygotes of HLA-DR2/non-DR4. The association with HLA-DR2/DR4 heterozygosity was highly significant in patients with SLE in whom the onset occurred under age 30 and there was no significant association in patients with SLE in whom the onset occurred at age over 30 years. The possible role of HLA-DR2/DR4 heterozygosity in the development of SLE is discussed.