During “nondamaging” exercise, skeletal muscle markedly releases interleukin (IL)‐6, and it has been suggested that one biological role of this phenomenon is to inhibit the production of tumor necrosis factor (TNF)‐α, which is known to cause pathogenesis such as insulin resistance and atherosclerosis. To test this hypothesis, we performed three experiments in which eight healthy males either rested (CON), rode a bicycle for 3 h (EX), or were infused with recombinant human IL‐6 (rhIL‐6) for 3 h while they rested. After 2.5 h, the volunteers received a bolus of Escherichia coli lipopolysaccharide endotoxin (0.06 ng/kg) i.v. to induce low‐grade inflammation. In CON, plasma TNF‐α increased significantly in response to endotoxin. In contrast, during EX, which resulted in elevated IL‐6, and rhIL‐6, the endotoxin‐induced increase in TNF‐α was totally attenuated. In conclusion, physical exercise and rhIL‐6 infusion at physiological concentrations inhibit endotoxin‐induced TNF‐α production in humans. Hence, these data provide the first experimental evidence that physical activity mediates antiinflammatory activity and suggest that the mechanism include IL‐6, which is produced by and released from exercising muscles.