Tumor necrosis factor-α (TNF) is believed to be an important mediator in many diseases that are associated with the sick euthyroid syndrome. To investigate the effect of TNF on thyroid hormone linetabolism, we performed a controlled study in six healthy postabsorptive males, in whom plasma thyroid hormones and TSH were sequentially measured after iv bolus injections of recombinant human TNF (50 μg/m²) and isotonic saline. During the 10.5-h study TNF produced the characteristic changes in circulating thyroid hormones and TSH observed in the sick eiuthyroid syndrome. Compared with the control experiment, TNF induced significant decreases in T₃ (−36 ± 2%; saline, −20 ± 3%; P < 0.05) and TSH levels (−68 ± 3%; saline, −44 ± 8%; P < 0.05) and a significant increase in rT₃ values (+48 ± 11%; saline, −12 ± 1%; P < 0.05). T₄ and free T₄ index were not affected by TNF. Free T₄ showed a mean transient increase of 18% in five subjects (nonsignificant), which occurred synchronically with a transient 3.5-fold rise in circulating FFA levels. Our results suggest that TNF is involved, either directly or indirectly, in the pathogenesis of the sick euthyroid syndrome.