Insulin-dependent diabetes mellitus (IDDM) is linked to HLA factors on human chromosome 6 and strongly associated with the presence of autoantibodies against the glutamic acid decarboxylase isoform GAD65. These autoantibodies, GAD65Ab are detected both before and at the time of clinical diagnosis. Molecular sequencing of HLA alleles and PCR-based genotyping have improved our understanding of the linkage between HLA and IDDM. At the same time, the molecular cloning of human islet GAD65 and the development of precise and reproducible GAD65Ab assays with recombinant human GAD65 has given new insights to the problem of to what extent HLA control the development of a GAD65 immune response or to the development of IDDM. Recent data are briefly reviewed. In new onset IDDM patients GAD65Ab were associated with the DQ2/8 or DQ2/X genotype. However, in patients with an older age at onset the association was particularly pronounced with the DQ2/8 genotype. The DQ5/8 genotype was significantly decreased among GAD65Ab positive patients. Certain DQ genotypes, therefore, seem permissive for the formation of GAD65Ab in IDDM. Studies of the general population is needed to determine if the DQ2, 8 or both alleles predispose to GAD65 autoreactivity. This is important since other factors may control the development of IDDM in only a fraction of GAD65 antibody positive individuals detected following a screening of the general population.