Objective: In this research, long-term exercise-trained and untrained rats underwent exhausting exercise. We compared muscle damage, interleukin-6 (IL-6) - a product of the muscle cell myoblast and satellite cells in response to muscle injury -,free oxygen radicals that have been reported to be responsible for this damage and, antioxidant levels in both groups. Materials and Methods: After exhausting exercise, trained and untrained rats were sacrificed by taking blood intracardiacally, just after exhaustion, one day and three days following exhaustion. Muscle damage was examined by light microscopy; the immune reactivity of the muscles was examined by IL-6 immunohistochemical evaluation and malondialdehite. Glutathione peroxidase levels of the muscles were assessed spectrophotometrically. Results: After exhaustion, the muscle damage was found to be higher in the untrained group than in the trained group. Maximum muscle damage, IL-6 immunoreactivity and oxidant levels emerged one day after exhaustion in both trained and untrained groups. The drop of oxidants, increase in antioxidants and the visualized regeneration process in histological samples appeared more significantly on day three after the exhaustion in trained animals compared to untrained animals. Three days after exhaustion, IL-6 and oxidant levels were found to decrease, and especially in the trained group, it approached approximately to the level of controls. In the acutely running untrained group, although IL-6 involvement decreased, plasma oxidant levels were still found to be significantly higher and antioxidant levels were lower compared to that in controls. Conclusion: This experiment revealed that the muscles of the exercise-trained rats were more resistant to this type of destructive muscle contraction than untrained rats. The IL-6 levels did not prominently increase just after the exhaustion but one day after exhaustion which made us think that the pro-inflammatory factors might have been suppressed by another agent - most probably by cortisol - in the beginning of the muscle damage and increased after the diminishing effects of these agents. © Turkish Journal of Physical Medicine and Rehabilitation, Published by Galenos Publishing.