In previous studies, interleukin-1 (IL-1) or tumor necrosis factor (TNF) have been demonstrated to augment skeletal muscle protein breakdown in a manner similar to that induced by bacterial endotoxin. This response to IL-1 or TNF was elicited only after they were administered to animals for various periods, as their addition in vitro to incubated muscles from normal untreated rats was without effect. This suggested that IL-1 and TNF may augment muscle proteolysis in an indirect fashion. Serum levels of IL-1, TNF as well as interleukin-6 (IL-6) are all elevated during infection induced by bacterial endotoxin. Both IL-1 and TNF can induce the synthesis of IL-6 by a variety of cells. Because of this, in the present report, the ability of IL-6 to stimulate skeletal muscle protein breakdown was examined. Muscle protein breakdown was evaluated by measuring the release of both tyrosine and 3-methylhistidine by incubated muscles. Pretreatment of rats with IL-6 for 6 hr induced fever and increased the release of both tyrosine and 3-methylhistidine by the extensor digitorum longus muscle. However, IL-6 did not augment muscle proteolysis when muscles from normal untreated rats were incubated in the presence of the cytokine. The data suggest that the acute treatment of animals with IL-6 can augment muscle proteolysis. Whether this response is due to a direct effect of IL-6 on the myocyte or whether it is due to the production of other mediators remains unclear.