Aim: Plasma interleukin-6 (IL-6) increases during exercise by release from active muscles and during prolonged exercise also from the brain. The IL-6 release from muscles continues into recovery and we tested whether the brain also releases IL-6 in recovery from prolonged exercise in humans. Additionally, it was evaluated in mice whether brain release of IL-6 reflected enhanced IL-6 mRNA expression in the brain as modulated by brain glycogen levels. Methods: Nine healthy male subjects completed 4 h of ergometer rowing while the arterio-jugular venous difference (a-v diff) for IL-6 was determined. The IL-6 mRNA and the glycogen content were determined in mouse hippocampus, cerebellum and cortex before and after 2 h treadmill running (N = 8). Results: At rest, the IL-6 a-v diff was negligible but decreased to -2.2 ± 1.9 pg ml(-1) at the end of exercise and remained low (-2.1 ± 2.1 pg ml(-1) ) 1 h into the recovery (P < 0.05 vs. rest). IL-6 mRNA was expressed in the three parts of the brain with the lowest content in the hippocampus (P < 0.05) coupled to the highest glycogen content (3.2 ± 0.8 mmol kg(-1) ). Treadmill running increased the hippocampal IL-6 mRNA content 2-3-fold (P < 0.05), while the hippocampal glycogen content decreased to 2.6 ± 0.6 mmol kg(-1) (P < 0.05) with no significant changes in the two other parts of the brain. Conclusion: Human brain releases IL-6 both during and in recovery from prolonged exercise and mouse data suggest that concurrent changes in IL-6 mRNA and glycogen levels make the hippocampus a likely source of the IL-6 release from the brain.