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Background: Adiponectin exhibits anti-inflammatory actions and is mainly expressed in adipose tissue. However, recent studies have shown that adiponectin can also be secreted by skeletal muscle fibers with autocrine and paracrine effects., Objectives: To analyze the role of adiponectin in the metabolic and inflammatory response of skeletal muscle after acute exhaustive aerobic exercise., Methods: C57BL/6 (WT) and adiponectin knockout (AdKO) mice underwent four days of treadmill running adaptation and at the fifth day, they performed an incremental maximum test to determine the maximum speed (Vmax). Acute exercise consisted of one hour at 60% Vmax. Mice were euthanatized 2 and 24 h after acute exercise session., Results: Serum and gastrocnemius adiponectin increased after 2-hours of acute exercise. NEFA concentrations were lower in non-exercise AdKO, and decreased 2-hours after exercise only in WT. No differences were found in muscle triacylglycerol content; however, glycogen content was higher in AdKO in non-exercise (p-value = 0.005). WT showed an increase in AMP-activated protein kinase (AMPK) phosphorylation 2-hours after exercise and its level went back to normal after 24-hours. Otherwise, exercise was not able to modify AMPK in the same way as in AdKO. WT showed an increase in the phosphorylation of ACC (Ser79) 2-hours after exercise and return to normal after 24-hours of exercise (p-value < 0.05), kinects that was not observed in AdKO mice. IL-10 and IL-6 concentration was completely different among genotypes. In WT, these cytokines were increased at 2 (p-value < 0.01) and 24 h (p-value < 0.001) after exercise when compared with AdKO. NF-κBp65 protein and gene expression were not different between genotypes., Conclusion: Adiponectin influences muscle metabolism, mainly by the decrease in exercise-induced AMPK phosphorylation, inflammatory profile and IL-6 in the muscle., (Copyright © 2019 Elsevier Ltd. All rights reserved.)