Background. The matrix metalloproteinases (MMPs) play a pivotal role in adverse left ventricular (LV) myocardial remodeling. The transmembrane protein, extracellular matrix metalloproteinase inducer (EMMPRIN), causes increased MMP expression in-vitro, and elevated levels occur in patients with LV failure. However, the direct consequences of a prolonged increase in the myocardial expression of EMMPRIN in-vivo remained unexplored. Methods/Results. Cardiac restricted EMMPRIN expression (EMMPRINexp) was constructed in mice using the full length human EMMPRIN gene ligated to the myosin heavy chain promoter, which yielded approximately a 2-fold increase in EMMPRIN when compared to age/strain matched wild type mice (WT), EMMPRINexp (n=27) and WT (n=33) mice were examined at 3.2±0.1 or at 13.3±0.5 months of age (n=43,26, respectively). LV end-diastolic volume (EDV) was similar in young EMMPRINexp and WT mice (54±2 vs 57±3 uL), but LV ejection fraction (EF) was reduced (51±1 vs 57±1 %, p<0.05). In old EMMPRINexp mice, LV EDV was increased when compared to old WT values (76±3 vs 58±3 uL, p<0.05), and LV EF was significantly reduced (45±1 vs 57±2 %, p<0.05). In EMMPRINexp old mice, myocardial MMP-2 and membrane type-1 MMP levels were increased by over 50% from WT values (p<0.05) and was accompanied by a 2-fold higher collagen content (p<0.05). Conclusions. Persistent myocardial EMMPRIN expression in aging mice caused increased levels of both soluble and membrane type MMPs, fibrosis, and was associated with adverse LV remodeling. These findings suggest that EMMPRIN is an upstream signaling pathway which can play a mechanistic role in adverse remodeling within the myocardium.