The role of interleukin-6 (IL-6) in carbohydrate metabolism beyond its inhibition of hepatic phosphoenolpyruvate carboxykinase has not been widely pursued. To describe such IL-6 effects, we examined in the rat the responses of plasma corticosterone, glucagon, insulin, and glucose levels and the hepatic glycogen content 30, 60, 90, 120, and 180 min after intravenous injection of recombinant human IL-6. The effect to increase plasma corticosterone was consonant with the well-known action of IL-6 on the hypothalamus-pituitary-adrenal cortex. IL-6 produced a transient increase in plasma glucagon that was mirrored by elevated plasma glucose and a depletion of hepatic glycogen. Plasma insulin levels were not elevated within the first hour after IL-6 injection but were significantly elevated 90 min and beyond. We suggest that the stimulus for increased circulating insulin was elevated plasma glucose, rather than a direct effect of IL-6. The results demonstrate that IL-6, acting directly on peripheral organs and/or through the central nervous system (CNS) can alter the hormonal and carbohydrate milieu. We propose that these actions of IL-6 are one aspect of its role in the acute phase response.