There is evidence that certain alleles at the HLA-DQ locus are correlated with susceptibility to insulin-dependent diabetes mellitus (IDDM) and in particular that DQ beta-chain alleles containing aspartic acid at position 57 are protective. The availability of a large group of patients with IDDM enabled us to assess the role of HLA-DQ alleles in susceptibility to the disease in order to confirm and extend recent observations derived from studies of smaller numbers of patients. Using allele-specific oligonucleotide probes and the polymerase chain reaction, we studied 266 unrelated patients with IDDM and 203 unrelated normal subjects for eight HLA-DQ beta-chain alleles. Two major findings emerged from these studies. First, the presence of an HLA-DQw1.2 allele was protective. Only 6 of the 266 patients with IDDM (2.3 percent) were positive for HLA-DQw1.2, as compared with 74 of the 203 normal subjects (36.4 percent; P less than 0.001). Thus, persons with the HLA-DQw1.2 allele, which is one of the polymorphic forms of the beta chain of the HLA-DQ molecule, rarely had IDDM, no matter which other HLA-DQ beta-chain allele they inherited ("dominant protection"). Second, the presence of the HLA-DQw8 allele increased the risk of IDDM. The relative risk of IDDM was 5.6 in persons homozygous for HLA-DQw8, and it was similar in persons with the HLA-DQw1.1/DQw8 or HLA-DQw2/DQw8 haplotype ("dominant susceptibility"). However, the relative risk of IDDM in persons who had the HLA-DQw1.2/DQw8 haplotype was 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8. We conclude that the presence of the HLA Class II antigen DQw1.2 is strongly protective against the development of IDDM, and that complete HLA-DQ typing is necessary for accurate assessment of susceptibility to IDDM.