Dilated cardiomyopathy (DCM) is characterized by dilatation of the ventricular chambers and impaired myocardial contractility. The results of our previous study indicated that a deficiency in matricellular cartilage oligomeric matrix protein (COMP) led to spontaneous and progressive DCM in mice via the ubiquitination/degradation of integrin β1. However, the specific ubiquitin enzyme involved in degradation of integrin β1 and the pathogenesis of DCM remain elusive. We first compared gene expression profiles in hearts from 3-month-old wild type and COMP^−/− mice using microarray analysis. Among the E3 ubiquitin ligases upregulated in COMP^−/− hearts, c-Cbl silencing rescued the ubiquitination/degradation of integrin β1, myofilament loss, apoptosis and connexin-43 deficiency in cardiomyocytes due to the silencing of COMP. Furthermore, c-Cbl silencing by intramyocardial injections of siRNA into 1-month-old COMP^−/− mice ameliorated spontaneous DCM in vivo, as evidenced by the inhibition of the dilation of ventricular chambers, impaired ejection fraction and myofilament loss. A subsequent cellular ubiquitination assay revealed that overexpression of c-Cbl induced ubiquitination of integrin β1, whereas the G306E mutation in c-Cbl, which prevented the binding of c-Cbl to its substrates, had no effect on integrin β1 ubiquitination, indicating that c-Cbl directly caused the ubiquitination of integrin β1 in the hearts. In conclusion, our results demonstrate that c-Cbl mediates the ubiquitination/degradation of integrin β1, which leads to COMP deficiency-induced DCM.