HLA antigens A, B, C, DR and BF were determined in 14 sibling pairs with type I diabetes and in 61 patients without familial risks. Significantly positive associations of the disease with HLA DR3 and DR4 and a negative association with DR2 were found. Positive and negative associations with the various HLA A, B and C antigens (A1, A2, B8, B15, B18, Cw3) are of a secondary nature due to strong genetic coupling with primarily associated DR alleles. Localisation of diabetes-associated genes in the HLA DR region could be demonstrated in two families with HLA recombinations. In both cases the hypothetic disease gene segregated with the HLA DR segment. Joint evaluation of these data in an international series involving 1200 type I diabetics showed furthermore that around 90% of all patients are DR3 and/or DR4 positive, that the highest morbidity risk exists in DR3/4 heterozygosity and that DR4 positive persons usually fall ill before their 20th year of life and frequently in the last 3 months of the year. Allotment of clinical, epidemiological, virological and immunological criteria of type I diabetes to only one of the both risk factors indicates heterogeneous immunopathogenesis of the disease. HLA DR3 predisposes particularly to endocrine autoimmune disease and DR4 to increased virus susceptibility.