Skeletal muscle, due to the presence of resident stem cells called satellite cells (SC), possesses a remarkable capacity for regeneration. The salience of this ability is most obvious in the context of dystrophic disease, which is characterized by chronic activation of SC-driven regenerative cycles for both repair of existing fibers, and de novo fiber generation. The assumption, which has never been tested using mouse genetics, has therefore been that loss of SCs would be uniformly detrimental in muscular dystrophy (MD). Here we generated a novel model of SC ablation and crossed it with mouse models of MD to directly investigate how critical these cells are in maintaining muscle viability during a chronic degenerative disorder. Long-term, SCs are required to maintain muscle size for survival in dystrophic mice because diseased myofibers dropped out over time and could not be replaced due to absence of de novo fiber generation. However, our models also revealed a previously unidentified pathological effect that SC activation, and presumably the associated fusion, have on the integrity and functionality of dystrophic myofibers. Pronounced improvements in histopathology and function were observed when SCs were ablated in 2-week-old dystrophic mice. Depletion of SCs beginning at 2 months of age provided similar improvements; these included enhanced sarcolemmal integrity, fewer damaged fibers, less myofiber central nucleation, decreased fibrosis and a dramatic increase in size of remaining myofibers. Dystrophic mice lacking SCs performed significantly better than those with SCs when exercised on a treadmill. Taken together these results clarify the role of SC-dependent regeneration in MD pathogenesis; while production of de novo fibers is an essential arm of the regenerative response, unexpectedly, SC-fusion with existing myofibers, which has been believed to be reparative, is not only dispensable but evidently detrimental to their health and function.