Acute inflammation is characterized by low serum T(3) and T(4) levels accompanied by changes in liver type 1 deiodinase (D1), liver D3, muscle D2, and muscle D3 expression. It is unknown at present whether thyroid hormone receptor alpha (TRalpha) plays a role in altered peripheral thyroid hormone metabolism during acute illness in vivo. We induced acute illness in TRalpha-deficient (TRalpha(0/0)) mice by administration of a sublethal dose of LPS. Compared with wild-type, TRalpha(0/0) mice have lower basal serum T(4) and lower liver D1 activity and muscle D3 mRNA expression, whereas liver D3 activity is higher. These changes are gender specific. The inflammatory response to LPS was similar in WT and TRalpha(0/0) mice. The decrease in serum thyroid hormones and liver D1 was attenuated in TRalpha(0/0) mice, whereas the LPS induced fall in liver D3 mRNA was more pronounced in TRalpha(0/0) mice. Muscle D2 mRNA increased similarly in both strains, whereas muscle D3 mRNA decreased less pronounced in TRalpha(0/0) mice. We conclude that alterations in peripheral thyroid hormone metabolism induced by LPS administration are partly regulated via TRalpha.