Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQαβ heterodimers composed of a DQα chain with anrginine at residue 52 (Arg52⁺) combined to a DQβ chain lacking an aspartic acid at residue 57 (Asp57⁻. With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8,115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52⁺ DQα/Asp57⁻ Dβp heterodimers, formed in cis and/r in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25–71.86, P < 10⁻. 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, Cl 17.05–95.9). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, Cl 12.88–96.78, P < 10⁻⁷). 4) The simultaneous expression of four different susceptibility heterodimers explains the highest risk of DR3-DQw2/DR4-DQw8 heterozygotes. In conclusion, there is a dose effect of cis- and trans-encoded HLA-DQαβ heterodimers in IDDM susceptibility influenced by the diversity of these molecules.