Necrosis of skeletal muscle fibers in the lethal childhood myopathy Duchenne muscular dystrophy (DMD) results from defects in the cell membrane-associated protein, dystrophin. This study tests the novel hypothesis that the initial sarcolemmal breakdown resulting from dystrophin deficiency is exacerbated by inflammatory cells and that cytokines, specifically tumor necrosis factor- (TNF), contribute to muscle necrosis. To block in vivo TNF bioactivity, young dystrophic mdx mice (a model for DMD) were injected weekly from 7 days of age with the anti-TNF antibody Remicade(R) before the onset of muscle necrosis and dystropathology that normally occurs at 21 days postnatally. The extent of inflammation, muscle necrosis, and myotube formation was measured by histological analysis from 18 to 28 days and muscle damage was also visualized by penetration of Evans blue dye into myofibers. Data from Remicade(R)-treated and control mdx mice were compared with mdx/TNF(-/-) mice that lack TNF. Pharmacological blockade of TNF activity with Remicade(R) clearly delayed and greatly reduced the breakdown of dystrophic muscle, in marked contrast to the situation in mdx and mdx/TNF(-/-) mice. Remicade(R) had no adverse effect on new muscle formation. Remicade(R) is a highly specific anti-inflammatory intervention, and clinical application to muscular dystrophies is suggested by this marked protective effect against skeletal muscle breakdown.