Alterations in cardiac extracellular matrix are involved in dilated cardiomyopathy (DCM) and its progression to heart failure. The matricellular protein cartilage oligomeric matrix protein (COMP) has been indicated localized in the heart. However, the role of COMP in cardiac homeostasis and disease remains elusive. COMP-/- mice, both male and female, developed DCM spontaneously at young age (3-5 months), with impaired cardiac function. Assessment of postnatal COMP-/- heart at 1 month, although functionally normal, revealed severe cardiac ultrastructure defect, in parallel with cardiomyocyte apoptosis, myofilament loss, connexin-43 deficiency and matrix metalloproteinase activation. Decreased COMP expression was observed in the heart sample of DCM patients compared with donor heart. Mechanistically, COMP-/- heart exhibited reduced integrin beta 1 expression and signaling. Ectopic expression of COMP or integrin beta 1 rescued COMP-deficiency- induced cardiomyocyte apoptosis, myofilament dissolution, and connexin-43 aberrance. Additionally, COMP directly bonded to the extracellular beta-tail domain of integrin beta 1, prevented integrin beta 1 ubiquitination/ degradation, and maintained the cardiac homeostasis. COMP-integrin beta 1 axis is a potential target of DCM.