Duchenne muscular dystrophy represents a severe inherited disease of striated muscle. It is caused by a mutation of the dystrophin gene and characterized by a progressive loss of skeletal muscle function. Most patients also develop a dystrophic cardiomyopathy, resulting in dilated hypertrophy and heart failure, but the cellular mechanisms leading to the deterioration of cardiac function remain elusive. In the present study, we tested whether defective excitation-contraction (E-C) coupling contributes to impaired cardiac performance. “E-C coupling gain” was determined in cardiomyocytes from control and dystrophin-deficient mdx mice. To this end, L-type Ca²⁺ currents (I_CaL) were measured with the whole cell patch-clamp technique, whereas Ca²⁺ transients were simultaneously recorded with confocal imaging of fluo-3. Initial findings indicated subtle changes of E-C coupling in mdx cells despite matched Ca²⁺ loading of the sarcoplasmic reticulum (SR). However, lowering the extracellular Ca²⁺ concentration, a maneuver used to unmask latent E-C coupling problems, was surprisingly much better tolerated by mdx myocytes, suggesting a hypersensitive E-C coupling mechanism. Challenging the SR Ca²⁺ release by slow elevations of the intracellular Ca²⁺ concentration resulted in Ca²⁺ oscillations after a much shorter delay in mdx cells. This is consistent with an enhanced Ca²⁺ sensitivity of the SR Ca²⁺-release channels [ryanodine receptors (RyRs)]. The hypersensitivity could be normalized by the introduction of reducing agents, indicating that the elevated cellular ROS generation in dystrophy underlies the abnormal RyR sensitivity and hypersensitive E-C coupling. Our data suggest that in dystrophin-deficient cardiomyocytes, E-C coupling is altered due to potentially arrhythmogenic changes in the Ca²⁺ sensitivity of redox-modified RyRs.