The proinflammatory cytokine, interleukin-1 (IL-1), has been implicated in the pathogenesis of several autoimmune and inflammatory diseases. One of its natural inhibitors, IL-1 receptor antagonist, is a potent antiinflammatory agent. We have previously described genetic associations between an allele of the IL-1 receptor antagonist gene (IL1RN*2) and several autoimmune and inflammatory diseases. In the present study, we tested the association of this polymorphism with thyroid diseases. We genotyped 2 separate cohorts (total of 100 patients) with Graves' disease and 58 patients with Hashimoto's thyroiditis and compared IL1RN*2 frequencies with those in 261 ethnically matched controls. There was a significant increase in IL1RN*2 frequency and carriage rate in Graves' disease, but this was not associated with thyroid antibody levels, T4 levels, thyroid-associated ophthalmopathy, or outcome after antithyroid drug treatment. In contrast, there was no difference in the frequency of IL1RN*2 between patients with Hashimoto's thyroiditis and the control group. Whether the IL1RN polymorphism makes a direct functional contribution to the pathogenesis of Graves' disease or is acting as a marker for a linked gene is being investigated.