Abstract: IDDM is positively associated with HLA‐DQA1*0301‐DQB1*0302 (DQ8) and DQA1*0501‐DQB1*0201 (DQ2) and negatively associated with DQA1*0102‐DQB1*0602 (DQ6). The aim of the present study was to analyze the importance of several polymorphic residues and domains of DQα and DQβ, in addition to residue 52 DQα and residue 57 DQβ, with regard to susceptibility or resistance in new‐onset 0‐ to 15‐year‐old Swedish children with IDDM (n= 425) and matched controls (n= 367). HLA genotyping identified several polymorphic residues of the DQα and DQβ to be either positively or negatively associated with IDDM, including Arg 52 DQα and Asp 57 DQβ. Leu 69 DQα was positively (OR 7.02, P < 0.0001), Ala 69 DQα was negatively (OR 0.22, P < 0.0001), Gln 47 DQα was positively (OR 5.8, P < 0.0001), Cys 47 DQα was positively (OR 2.2, P < 0.0001), Lys 47 DQα was negatively (OR 0.47, P < 0.005), and Arg 47 DQα was negatively (OR 0.22, P < 0.005) associated with IDDM. Similarly, residues at 11, 18, 45, 48, 50, 53, 55, 61, 64, 66, 76, and 80 were either positively or negatively associated with IDDM. Likewise, for DQβ, Leu 53 DQβ was positively (OR 11.01, P < 0.0001), Gln 53 DQβ was negatively (OR 0.22, P < 0.0005), Arg 70 DQβ was positively (OR 11.01, P < 0.0001), and Gly 70 DQβ was negatively (OR 0.19, P < 0.0001) associated like other residues at 71, 74, 84, 85, 86, 89, and 90 DQβ with IDDM. Certain domains in the DQα, RFTIL (at DQα positions 52, 61, 64, 66, and 69), were present in 95% of patients compared to 69% of controls (OR 9.01, Pc < 0.0001), and DQβ domain GR (at DQβ positions 45 and 70) was present in 95% of patients and 68% of controls (OR 8.68, P < 0.0001), which correlated better than the individual amino acid residues with IDDM. A combination of the DQα and DQβ chain domains was present in 94% of patients compared to 60% of controls (OR 10.6, P < 0.001). In conclusion, domains in the DQα, DQβ, or both in the DQ molecule explain susceptibility or resistance to IDDM better than individual amino acid residues of DQA1 and DQB1.