Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1* 03-DQB1* 02/DRB1* 0401-DQB1* 0302 genotype is often found to be higher than for the individual DRB1* 03-DQB1* 02 and DRB1* 0401-DQB1* 0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ (α1, β1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1* 0401-DQB1* 0302-positive genotypes relative to the DRB1* 03-DQB1* 02-positive genotypes is different from that of DRB1* 01-DQB1* 0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1* 01-DQB1* 0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of trans-encoded HLA DQ molecules in the determination of HLA-associated risk in T1D.