CollagenVI is a non-fibrillar collagen present in the extracellular matrix (ECM) as a complex polymer; the mainly expressed form is composed of α1, α2 and α3 chains; mutations in genes encoding these chains cause myopathies known as Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM). The collagenVI α6 chain is a recently identified component of the ECM of the human skeletalmuscle. Here we report that the α6 chain was dramatically reduced in skeletalmuscle and muscle cell cultures of genetically characterized UCMD, BM and MM patients, independently of the clinical phenotype, the gene involved and the effect of the mutation on the expression of the „classical“ α1α2α3 heterotrimer. By contrast, the collagenVI α6 chain was normally expressed or increased in the muscle of patients affected by other forms of muscular dystrophy, the overexpression matching with areas of increased fibrosis. In vitro treatment with TGF-β1, a potent collagen inducer, promoted the collagenVI α6 chain deposition in the ECM of normal muscle cells, whereas, in cultures derived from collagenVI-related myopathy patients, the collagenVI α6 chain failed to develop a network outside the cells and accumulated in the endoplasmic reticulum. The defect of the α6 chain points to a contribution to the pathogenesis of collagenVI-related disorders.