Pathologic cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathologic cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk, and represents an important yet underdeveloped target of therapeutic research. Recently we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally-induced pathologic cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular-assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in 2 independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression by trans-aortic constriction (TAC) reversal; and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analysis, we found that upon TAC release, cardiac mass and cardiomyocyte cross sectional areas in MuRF1 -/- mice decreased ~70% less than in wild type mice in the 4 weeks after release. This was in striking contrast to wild type mice who returned to baseline cardiac mass and cardiomyocytes size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by MHC, smooth muscle actin, and BNP was attenuated similarly in both MuRF1 -/- and wild type hearts after TAC release. In the second model, MuRF1 -/- mice also displayed resistance to dexamethasone-induced cardiac atrophy as determined by echocardiographic analysis. These studies demonstrate for the first time that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic regression of cardiac hypertrophy and dexamethasone-induced atrophy.