High-intensity exercise induces oxidative stress and inflammatory events in muscles. Tumor necrosis factor (TNF)-α may alter muscle protein metabolism or promote muscle regeneration. We hypothesized that a program of noninvasive chronic inspiratory loading of different intensities induces a differential pattern of physiological, molecular, and cellular events within rat diaphragms. Antioxidants and TNF-α blockade may influence those events. In the diaphragm, gastrocnemius, and blood of rats exposed to high-intensity inspiratory threshold loads (2 hour every 24 hours for 14 days), with and without treatment with N-acetyl cysteine or infliximab (anti-TNF-α antibody), inflammatory cells and cytokines, superoxide anion production, myogenesis markers, and muscle structure were explored. In all animals, maximum inspiratory pressure (MIP) and body weight were determined. High-intensity inspiratory loading for 2 weeks caused a decline in MIP and body weight, and in the diaphragm induced a reduction in fast-twitch fiber proportions and sizes, whereas inflammatory cells and cytokine levels, including TNF-α immunohistochemical expression, superoxide anion, internal nuclei counts, and markers of myogenesis were increased. Blockade of TNF-α improved respiratory muscle function and structure, and animal weight, and, in the diaphragm, reduced inflammatory cell numbers and superoxide anion production drastically while inducing larger increases in protein and messenger RNA levels and immunohistochemical expression of TNF-α, internal nuclei, and markers of muscle regeneration. Blunting of TNF-α also induced a reduction in blood inflammatory cytokines and superoxide anion production. We conclude that TNF-α synthesized by inflammatory cells or myofibers could have differential effects on muscle structure and function in response to chronic, noninvasive, high-intensity inspiratory threshold loading.