In contrast to H2-based susceptibility to experimental autoimmune thyroiditis (EAT) induced with thyroglobulin (Tg), human leukocyte antigen (HLA) association with Hashimoto's thyroiditis, the human counterpart, is less clear, and determining association is further complicated by DR/DQ linkage disequilibrium. Previously, we addressed the controversial implication of HLA-DR genes by introducing HLA-DRA/DRB1*0301 (DR3) transgene into endogenous class II negative H2Ab(0) mice. EAT induction with either human (h) or mouse (m) Tg demonstrated the permissiveness of DR3 molecules for shared Tg epitopes. Here, we examined the participation of HLA-DQ genes by introducing DQA1*0301/DQB1*0302 (DQ8) transgene into class II negative Ab(0) or class I and II negative beta(2)m((-/-)) Ab(0) mice. About 50% and 80% of HLA-DQ8(+) Ab(0) and beta(2)m(-) Ab(0) mice, respectively, developed moderate EAT after hTg immunization, but only minimal response to mTg. The hTg presentation to hTg-primed cells was blocked by anti-DQ mAb in vitro. By contrast, HLA-DRB1*1502 (DR2) and *0401 (DR4) transgenes contributed little to hTg induction. Similarly, DQA1*0103/DQB1*0601 or DQA1*0103/DQB1*0602 (DQ6) transgenic Ab(0) mice were unresponsive to hTg induction and carried no detectable influence in DQ8/DQ6 double transgenic mice. Thus, both HLA-DR and -DQ polymorphism exists for hTg in autoimmune thyroiditis. The use of defined single or double transgenic mice obviates the complications seen in polygenic human studies.