Introduction: SGLT2 inhibitors cause weight loss, and reduce epicardial adipose tissue (EAT) on T2DM. The effects of T2DM on non-diabetic HFrEF remain unclear. Methods: HFrEF was induced in non-diabetic pigs via percutaneous oclusion of LAD (LVEF 30±4%). Animals were randomized to empagliflozin 10mg daily or placebo (n=8/group) for 2 months, and animals were subsequently euthanized. Cardiac MRI and echocardiography were performed before and after treatment. Invasive hemodynamics, histology and molecular biology were performed at 2-months. Primary culture of adipocytes from EAT was performed. Results: Empagliflozin caused reverse LV remodeling, reduced LVEDV and improved LVEF (Table). EAT volume was inversely associated with myocardial consumption of free fatty acids (r=-0.6, p=<0.05). Empagliflozin reduced EAT, both as MRI-determined EAT volume and histologically-evaluated adipocyte size (Table). Empagliflozin induced lipolysis in the adipocytes from EAT, as demonstrated by lower levels of triglycerides and perilipin (main protein responsible for triglyceride storage), and higher levels of the lipolytic enzymes lipoprotein lipase and hormone-sensitive lipase. Empagliflozin caused an anti-inflammatory effect on EAT as shown by lower levels of macrophage infiltration and MCP-1. Empagliflozin exerted antioxidant actions, as per reduced levels of 8-OH-deoxyguanosine and malonildealdehide (oxidative stress markers in nuclei and protein, respectively. Conclusions: Empagliflozin exerts multiple benefits on EAT in non-diabetic HFrEF. Empagliflozin induces a lipolytic state that reduces EAT volume, and it also ameliorates the oxidative and inflammatory status of EAT.