Abstract Body (Do not enter title and authors here): CREG1 is a small glycoprotein predominantly localized in the endolysosomal system. In mouse heart, CREG1 expression increases with age. We previously observed cardiac hypertrophy and ventricular non-compaction in a small percentage of constitutive Creg1 knockout mice during the neonatal stage. To elucidate the physiological function of CREG1 in the heart, we generated cardiomyocyte-specific Creg1 knockout (cmCreg1KO) and knock-in (cmCREG1KI) mice by crossing Creg1^fl/fl and Rosa^{hCREG1/hCREG1} with Myh6-Cre mice, respectively. By 6 months of age, the cmCreg1KO mice developed severe myocardial interstitial fibrosis. Echocardiography at 10 months revealed markedly dilated left ventricles and significantly reduced ejection fractions. All the cmCreg1KO mice succumbed to heart failure between 10-12 months, while Creg1^fl/fl control littermates exhibited no obvious cardiac abnormalities. Necropsy of deceased cmCreg1KO mice showed increased heart-to-body weight ratios, enlarged cardiac chambers, and left atrial thromboses. Electron microscopy revealed sparse and elongated myofibers, scant and bizarre-shaped mitochondria, empty cytoplasm, and increased interstitial collagen accumulation. The cmCREG1KI mice exhibited better endurance to nutritional deprivation than Rosa^{hCREG1/hCREG1} littermate controls. In sharp contrast to cmCreg1KO hearts, cmCREG1KI and Rosa^{hCREG1/hCREG1} control hearts displayed very mild fibrosis at 8 months, suggesting that CREG1 overexpression may confer cardioprotective effects. In cultured cardiomyocytes, CREG1 colocalizes with the autophagosome marker LC3B following serum deprivation. Immunofluorescence microscopy demonstrated a marked reduction of LC3B puncta in cmCreg1KO hearts. Analysis of autophagic flux using CAG-RFP-EGFP-LC3 transgenic mice and immunoblotting indicated that the absence of CREG1 impairs both autophagosome formation and degradation, whereas knock-in of CREG1 enhances these autophagic processes. These findings suggest that CREG1 promotes autophagy and protects the heart from age-dependent dilated cardiomyopathy.