The cytokine interleukin (IL)-6 has recently been linked with type 2 diabetes mellitus and has been suggested to affect glucose metabolism. To determine whether acute IL-6 administration affects whole-body glucose kinetics or muscle glucose uptake, 18 healthy young men were assigned to one of three groups receiving a high dose of recombinant human IL-6 (HiIL-6; n = 6), a low dose of IL-6 (LoIL-6; n = 6) or saline (Con; n = 6) infused into one femoral artery for 3 h. The stable isotope [6,6-2H2] glucose was infused into a forearm vein throughout the 3 h infusion period and for a further 3 h after the cessation of infusion (recovery) to determine endogenous glucose production and whole-body glucose disposal. Infusion with HiIL-6 and LoIL-6 resulted in a marked (P < 0.05) increase in systemic IL-6 concentration throughout the 3 h of infusion (mean arterial plasma [IL-6]s of 319 and 143 pg ml-1 for HiIL-6 and LoIL-6, respectively), followed by a rapid decline (P < 0.05) during the recovery period. Subjects experienced clinical symptoms such as shivering and discomfort during HiIL-6 administration, but were asymptomatic during LoIL-6 administration. In addition, only HiIL-6 elevated (P < 0.05) plasma adrenaline (epinephrine). IL-6 infusion, irrespective of dose, did not result in any changes to endogenous glucose production, whole-body glucose disposal or leg- glucose uptake. These data demonstrate that acute IL-6 administration does not impair whole-body glucose disposal, net leg-glucose uptake, or increase endogenous glucose production at rest in healthy young humans.