Cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL-2), IL-6, and interferon-alpha (IFN-alpha), alter human thyroid hormone metabolism and may be involved in the pathogenesis the euthyroid sick syndrome. Experimental data suggest that interferon-gamma (IFN-gamma) could be another cytokine that might influence thyroid hormone metabolism. To evaluate whether IFN-gamma can be involved in the pathogenesis of the alterations in thyroid hormone metabolism in humans with nonendocrine illness, we measured thyroid hormone concentrations in six healthy volunteers during 24 hours in a placebo controlled trial: once after subcutaneous administration of IFN-gamma (Immukine, [Boehringer Ingelheim GmbH, Ingelheim/Rheim, Germany] 100 microg/m2 subcutaneous) and once after the administration of saline (control). In addition, we measured cytokine concentrations in plasma (TNF-alpha and IL-6). IFN-gamma did not induce effects on any of the measured thyroid hormone and thyroid-stimulating hormone (TSH) plasma concentrations. Moreover, IFN-gamma did not affect TNF-alpha plasma levels. Only a modest but significant elevation of plasma IL-6 levels was detected after administration of IFN-gamma (p < 0.05 vs. control). It is concluded that IFN-gamma administration to healthy humans does not result in short term alterations of thyroid hormone metabolism. These data do therefore not support a role of IFN-gamma in the pathogenesis of the euthyroid sick syndrome in humans as might be deduced from in vitro and in vivo animal studies.