The pathogenesis of insulin-dependent diabetes mellitus (IDDM) will remain obscure until the number of genetic mechanisms contributing to susceptibility can be clarified. Australian multiple-case families of IDDM have been examined for concordance in IDDM and HLA haplotypes and analysed for goodness-of-fit to hypotheses of one or two high-risk susceptibility genes. Diabetic siblings are HLA-identical in 75% of cases, confirming the association between HLA and IDDM, and suggesting recessively in inheritance of IDDM susceptibility. However, the most striking finding is that 52% of IDDM offspring are positive for both HLA-DRW3 and DRW4, compared with only 8% of their non-diabetic sibs and 1% of the general population. The risk for IDDM for the HLA-DRW3/DRW4 heterozygote is 37.2, and the chance that a child from a multiple-case family of IDDM will himself develop the disease is 6.5 times as great if he is a HLA-DRW3/DRW4 heterozygote than if he is not positive for both antigens. Possible genetic mechanisms are discussed, but the present data strongly support the interaction of two HLA-DR associated susceptibility genes in IDDM and rejects the hypothesis of a single autosomal recessive susceptibility gene.