Duchenne muscular dystrophy is caused by the absence of the protein dystrophin. Dystrophin's function is not known, but its cellular location and associations with both the force-generating contractile core and membrane-spanning entities suggest a role in mechanically coupling force from its intracellular origins to the fiber membrane and beyond. We report here the presence of destructive contractile activity in lumbrical muscles from dystrophin-deficient (mdx) mice during nominally quiescent periods following exposure to mechanical stress. The ectopic activity, which was observable microscopically, resulted in longitudinal separation and clotting of fiber myoplasm and was absent when calcium (Ca²⁺) was removed from the bathing medium. Separation and clotting of myoplasm were also produced in dystrophin-deficient muscles by local application of a Ca²⁺ ionophore to create membrane breaches in the absence of mechanical stress, whereas muscles from control mice tolerated ionophore-induced entry of Ca²⁺ without damage. These observations suggest a failure cascade in dystrophin-deficient fibers that 1) is initiated by a stress-induced influx of extracellular Ca²⁺, causing localized activation to continue after cessation of stimulation, and 2) proceeds as the persistent local activation, combined with reduced lateral mechanical coupling between the contractile core and the extracellular matrix, results in longitudinal separation of myoplasm in nonactivated regions of the fiber. This mechanism invokes both the membrane stabilization and the mechanical coupling functions frequently proposed for dystrophin and suggests that, whereas the absence of either function alone is not sufficient to cause fiber failure, their combined absence is catastrophic.