During illness, major changes in thyroid hormone metabolism and regulation occur; these are collectively known as non-thyroidal illness and are characterized by decreased serum triiodothyronine (T3) and thyroxine (T4) without an increase in serum TSH. Whether alterations in the central part of the hypothalamus–pituitary–thyroid (HPT) axis precede changes in peripheral thyroid hormone metabolism instead of vice versa, or occur simultaneously, is presently unknown. We therefore studied the timecourse of changes in thyroid hormone metabolism in the HPT axis of mice during acute illness induced by bacterial endotoxin (lipopolysaccharide; LPS). LPS rapidly induced interleukin-1β mRNA expression in the hypothalamus, pituitary, thyroid and liver. This was followed by almost simultaneous changes in the pituitary (decreased expression of thyroid receptor (TR)-β2, TSHβ and 5-deiodinase (D1) mRNAs), the thyroid (decreased TSH receptor mRNA) and the liver (decreased TRβ1 and D1 mRNA). In the hypothalamus, type 2 deiodinase mRNA expression was strongly increased whereas prepro-TRH mRNA expression did not change after LPS. Serum T3 and T4 fell only after 24 h. Our results suggested almost simultaneous involvement of the whole HPT axis in the downregulation of thyroid hormone metabolism during acute illness.