The purpose of our study was to evaluate what kind of relationships exist between HLA antigens and insulin-dependent diabetes mellitus (IDDM), in 20 families and in 40 single patients coming from and living in North Eastern Italy. The subjects studied show a strong association with HLA-DR3 and/or -DR4; at least one of these antigens is present in 88% of the diabetic subjects; this confirms that these antigens play a role in the pathogenesis of IDDM. We also noticed a negative association between IDDM and DR5 rather than DR2 and DR7. This result supports the hypothesis of a specific protective effect of DR5, at least as regards the population studied. Possibly, the gene(s) hypothetically involved in the protection against IDDM is (are) in linkage disequilibrium with DR2 and/or DR7 in some Caucasian populations and with DR5 in others. Another important result is the frequent HLA identity (75% of cases) among diabetic siblings of the same families. This result indicates that HLA identity is the main condition responsible for the susceptibility to the disease in the healthy siblings with HLA antigens identical to the diabetic siblings.