NOD.H-2h4 mice, which express I-Akon the NOD genetic background, spontaneously develop autoimmune thyroiditis (SAT) and anti-mouse thyroglobulin (MTg) autoantibodies. The incidence of SAT is nearly 100% in mice of both sexes 6–8 weeks after administration of 0.05% NaI in the drinking water. After reaching maximum severity, inflammation is chronic over the next 3–4 months. All mice that develop thyroid lesions also produce MTg-specific IgG1 and IgG2b autoantibodies. Thyroid lesions and anti-MTg autoantibodies did not develop in CBA/J (H-2k) or NOD.SWR(H-2q) mice after administration of NaI water. Both CD4+and CD8+T cells are involved in the initial development of SAT. Depletion of CD4+, but not CD8+, T cells after thyroid lesions have developed also markedly reduced SAT severity, indicating that CD4+T cells are required for both developing and maintaining SAT. Analysis of cytokine gene expression indicated that both Th1 and Th2 cytokines were expressed in thyroids of NOD.H-2h4 mice with SAT. Th1 and proinflammatory cytokines were maximally expressed 4–6 weeks after mice began receiving NaI water, while Th2 cytokine gene expression was greatest at 8–15 weeks, when lesions had reached maximal severity and were in the chronic phase. TGF-β was highly expressed in NOD.H-2h4 thyroids, irrespective of whether the mice had received NaI water or had thyroid lesions.