CONTEXT: Obesity and type 2 diabetes mellitus are associated with increased levels of IL-6, a marker of inflammation. OBJECTIVE: This study addressed the question of whether IL-6 was released from skeletal muscle after a high-fat meal in men with impaired glucose tolerance (IGT), a prediabetic state, and whether IL-6 release could be reduced by weight loss. DESIGN: Skeletal muscle metabolism was studied in men with IGT (n = 11) and compared with men with normal glucose tolerance (NGT, n = 9), matched for body mass index and age. IL-6 flux over skeletal muscle was measured with the forearm model. Eight IGT men were willing to participate in a 12-wk weight loss program and were tested again. RESULTS: IL-6, but not C-reactive protein or TNF-alpha receptor 1 and 2, was released by skeletal muscle. Muscle IL-6 release was higher in IGT than in NGT during fasting (IGT = 2.26 +/- 1.89 vs. NGT = 0.87 +/- 0.48 fmol x 100 ml tissue(-1) x min(-1), P = 0.04) and after a meal (mean area under the curve per minute: IGT = 3.48 +/- 2.63 vs. NGT = 1.37 +/- 0.75 fmol x 100 ml tissue(-1) x min(-1); P = 0.03). In the IGT men, body weight loss resulted in a decrease of postprandial IL-6 release from skeletal muscle (-52%; P = 0.04), reaching levels of the obese, NGT controls. CONCLUSION: The present data suggest that a high-fat meal can evoke IL-6 release from muscle and that the IL-6 release is a consequence rather than a cause of the obese, insulin-resistant, and/or IGT state.