Cytokines are thought to be involved in the pathogenesis the euthyroid sick syndrome. Experimental data from in vitro and animal in vivo studies suggest that interferon-gamma (IFN-gamma) could be another cytokine that might influence thyroid hormone metabolism, although in a previous study in healthy subjects we could not demonstrate an effect of IFN-gamma on thyroid hormone indices. Possibly, however, a non-stressed system is not a representative environment to study the effects of a mediator, which might exert its role during pathological circumstances in which it may interact synergistically with other inflammatory mediators. Therefore, we studied the effects of a single dose of recombinant human IFN-gamma (Immukine, 100 microg/m2, sc) on thyroid hormone concentrations in a placebo-controlled trial in 13 major surgery patients. Basal IFN-gamma levels did not increase. IFN-gamma induced a significant increase in monocyte HLA-DR expression (post-operative 50%; 24 h after IFN-gamma 90%), but did not affect thyroid hormone and thyroid stimulating hormone concentrations. We therefore conclude that IFN-gamma does not appear to be involved in the major changes in thyroid hormone metabolism in patients with non-thyroidal illness.