In this study, the hypothesis that the release of interleukin (IL)-6 from human muscle is linked to exercise intensity and muscle glucose uptake was investigated. In the overnight fasted state, seven healthy males performed knee extension exercise, kicking with both legs, each at 25 % of maximal power (W(max)) for 45 min (eliciting 23 +/- 1 % of pulmonary maximal oxygen uptake, V(O2,max)) and then simultaneously with one leg at 65 % and the other leg at 85 % W(max) for 35 min (40 +/- 1 % of pulmonary V(O2,max)). Blood was sampled from a femoral artery and both femoral veins, and blood flow was determined by thermodilution. Thigh plasma flow (0.15 +/- 0.01, 1.4 +/- 0.2, 2.0 +/- 0.1 and 2.3 +/- 0.2 l min(-1) thigh(-1) at rest and 25 %, 65 % and 85 % W(max), respectively) and thigh oxygen uptake (0.02 +/- 0.01, 0.27 +/- 0.03, 0.48 +/- 0.04 and 0.55 +/- 0.05 l min(-1) thigh(-1) at rest and 25 %, 65 % and 85 % W(max), respectively) increased with increasing exercise intensity (P < 0.05). Also, thigh IL-6 release (0.4 +/- 0.1, 1.3 +/- 0.5, 1.5 +/- 0.6 and 2.5 +/- 0.7 ng min(-1) thigh(-1) at rest and 25 %, 65 % and 85 % W(max), respectively) and thigh glucose uptake (0.05 +/- 0.01, 0.3 +/- 0.05, 0.75 +/- 0.16, 1.07 +/- 0.15 mmol min(-1) thigh(-1) at rest and 25 %, 65 % and 85 % W(max), respectively) increased with increasing exercise intensity (P < 0.05). During the last 35 min of exercise, arterial catecholamine concentrations were higher (P < 0.05) than at rest and during low-intensity exercise. During exercise, thigh IL-6 release was positively related to both thigh glucose uptake (P < 0.001) and thigh glucose delivery (P < 0.005), but not to thigh glucose extraction. Thigh IL-6 release was also positively related to arterial plasma adrenaline concentration. The pre-exercise muscle glycogen concentration tended to correlate with the arteriovenous IL-6 concentration difference at rest, and the postexercise glycogen concentration was inversely correlated with IL-6 release during the final 35 min of exercise. In conclusion, the study indicates that IL-6 release from human muscle is positively related to exercise intensity, arterial adrenaline concentration and muscle glucose uptake. This supports the hypothesis that IL-6 may be linked to the regulation of glucose homeostasis during exercise. The observation of a relationship between IL-6 release and muscle glycogen store both at rest and after exercise suggests that IL-6 may act as a carbohydrate sensor.