Subacute granulomatous thyroiditis (SAT) is a self-limiting systemic inflammatory disorder with possible transient expression of thyroid antibodies. Persistent hypothyroidism is uncommon. The interleukin-1 receptor antagonist IL-1ra is an inhibitor of IL-1 activity and allele 2 of the IL-1ra gene is associated with inflammatory diseases and IL-1ra production. Forty-eight subjects with SAT were investigated. Polymorphisms of IL-1ra, IL-1beta-511 and TNFalpha genes were studied with respect to thyroid peroxidase antibodies (TPOab), thyroglobulin antibodies, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Serum IL-1ra levels were measured. An increased allelic frequency (43% vs 22%, p=0.039) and carriage rate (79% vs 41%, p=0.018) for IL-1ra allele 2 were observed with expression of TPOab in 14 (29.2%) subjects compared with those with negative findings. The carriage rate for both IL-1ra allele 2 and IL-1beta-511 allele 2 was also increased with TPOab expression (71% vs 27%, p=0.004, respectively). No difference in allele frequency or carriage rate was found compared with healthy controls. Serum IL-1ra levels correlated with S-CRP (r=0.41, p=0.004) and ESR (r=0.34, p=0.016), but the association with genes or thyroid antibodies was statistically insignificant. S-CRP levels and ESR were lower and negatively correlated with expression of TPOab (r=-0.27, p=0.046 and r=-0.32, p=0.017). This study describes the multiplicity of the mechanisms responsible for the severity of the acute-phase response during the course of SAT. IL-1ra may have a significant anti-inflammatory role in SAT. Presence of IL-1ra allele 2 increases the risk of developing TPOab.