Increases in circulating interleukin-6 (IL-6) during exhaustive exercise have been suggested to be related to declining muscle glycogen. We addressed two hypotheses: (a) exhaustive exercise on two occasions will result in similar decreases in glycogen and increases in circulating IL-6 and its muscle mRNA; (b) increasing the rate of glycogen restoration via high-carbohydrate feeding in recovery will be associated with more rapid declines in muscle mRNA and circulating IL-6. Ten male subjects (22.6+/-0.8 year) cycled to exhaustion (65% VO(2 max)) on two occasions (117.8+/-2.9 min). Carbohydrate (1 g/kg bw) or water was ingested at exhaustion, 60, 120, 180, and 240 min post-exercise. Muscle biopsies were taken at rest, exhaustion, 30, 60, 120 and 300 min of recovery. Exercise resulted in a 14.5-fold increase (P<0.05) in IL-6 mRNA, 14.4-fold increase (P<0.05) in circulating IL-6, and a 80% decrease (P<0.05) in muscle glycogen from rest. The decline in glycogen was not correlated with the increase in IL-6 or IL-6 mRNA. During recovery, circulating IL-6 and its muscle mRNA decreased similarly in both trials; however, glycogen increased 150% (P<0.05) and 40% in the carbohydrate and water trials, respectively. Therefore, the declining IL-6 mRNA and IL-6 plasma concentrations during recovery were not related to carbohydrate availability or changes in glycogen.