Cardiomyopathies are a diverse group of primary cardiac diseases, most of which have a poorly understood etiology. One type of hereditary cardiomyopathy is caused by defects in the dystrophin gene in Duchenne and Becker muscular dystrophy patients. Our laboratory has identified a complex of dystrophin-associated proteins in skeletal and cardiac muscle which span the sarcolemma, linking the subsarcolemmal cytoskeleton to the extracellular matrix. The absence of dystrophin in Duchenne muscular dystrophy patients leads to the loss of dystrophin-associated proteins in both skeletal and cardiac muscle, suggesting that a primary loss of one or more dystrophin-associated proteins might lead to other forms of cardiomyopathy. Here we report the specific deficiency of the 50-kDa dystrophin-associated glycoprotein in cardiac and skeletal muscles of the BIO 14.6 strain of cardiomyopathic hamsters, which experience both autosomal recessive cardiomyopathy and myopathy. Other dystrophin-associated proteins are well preserved in myopathic hamster skeletal muscle, but the link between dystrophin and dystroglycan is disrupted. All dystrophin-associated proteins are decreased in abundance in the cardiomyopathic hamster heart, perhaps explaining why the cardiomyopathy is more severe than the myopathy. Thus, the disruption of the dystrophin-glycoprotein complex may play a role in skeletal and cardiac myocyte necrosis of the cardiomyopathic hamster.