To determine whether endotoxin-induced activation of type 2 iodothyronine deiodinase (D2) in the mediobasal hypothalamus is dependent upon circulating levels of corticosterone, the effect of bacterial lipopolysaccharide (LPS) on D2 gene expression was studied in adrenalectomized, corticosterone clamped adult, male Sprague-Dawley rats. In sham-adrenectomized animals, LPS (250 µg/100 g BW) increased circulating levels of corticosterone and IL-6, as well as tanycyte D2 mRNA in the mediobasal hypothalamus. Adrenalectomized, corticosterone clamped animals showed no significant rise in corticosterone following LPS compared to saline-treated controls, but increased IL-6 levels and tanycyte D2 mRNA similar to LPS-treated sham controls. To further clarify the potential role of corticosterone in the regulation of D2 gene expression by LPS, animals were administered high doses of corticosterone to attain levels similar to that observed in the LPS-treated group. No significant increase in D2 mRNA was observed in the mediobasal hypothalamus with the exception of a small subpopulation of cells in the lateral walls of the third ventricle. These data indicate that the LPS-induced increase in D2 mRNA in the mediobasal hypothalamus is largely independent of circulating corticosterone, and indicate that mechanisms other than adrenal activation are involved in the regulation of most tanycyte D2-expressing cells by endotoxin.