CD8⁺CD25⁺-activated cytotoxic T cells and anti-thyroglobulin antibodies (TgAb) are independently involved in the severity of Hashimoto's disease (HD). Interferon γ (IFN-γ) activates cytotoxic T cells. To evaluate the hypothesis that the functional +874A/T polymorphism in the gene encoding IFN-γ is associated with the severity of HD, we examined the frequencies of this polymorphism in 34 HD patients who developed hypothyroidism (severe HD); 22 untreated, euthyroid HD patients (mild HD); 49 patients with intractable Graves' disease (GD); 16 GD patients in remission; and 57 healthy volunteers. Frequency of the +874T allele, which is associated with high IFN-γ production, was higher in patients with severe HD than in those with mild HD (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.0-12.4; p = 0.047), but there was no difference in the frequency between GD patients. The difference in the frequency of +874T was observed in the subset of patients with HD negative for TgAb (OR, 8.4; 95% CI, 1.2-57.3; p = 0.029) but not in the subset of patients with HD positive for TgAb. Our data indicate that the +874A/T polymorphism in the IFN-γ gene is associated with severity of HD.