We previously proposed that the HLA-related genetic susceptibility to insulin dependent diabetes mellitus (IDDM) is best explained by at least two different susceptibility alleles, one preferentially associated with DR3, the other with DR4. This IDDM HLA heterogeneity model predicts that HLA haplotype sharing among affected sibpairs will be increased when the index case is a compound heterozygote (i.e., DR3/DR4). This prediction was tested and confirmed using the GAW IV IDDM data set. A significantly increased sharing of HLA haplotypes was seen when the index sib was DR3/DR4 compared to those of other genotypes (68% versus 37% sharing 2 haplotypes, p less than .01).