Cardiac ISG15 is controlled by type I IFN signaling, and ISG15 or ISGylation is upregulated in mice with transverse aortic constriction or infused with angiotensin II; rats with uninephrectomy and DOCA-salt, or pulmonary artery banding; cardiomyocytes exposed to IFNs or CD4+ T cell–conditioned medium; and ventricular tissue of humans with nonischemic cardiomyopathy. This evidence concerns the gene ISG15 and nonischemic cardiomyopathy.