OBJECTIVE Epicardial adipose tissue (EAT) in coronary artery disease is insulin resistant and has a proinflammatory profile. This study examined the regulation of EAT by exogenous omentin and its consequence on vascular cells. METHODS Stromal vascular cells (SC) of EAT and subcutaneous adipose tissue (SAT) from patients who underwent heart surgery were cultured and exposed to adipogenic factors with or without omentin. Proinflammatory cytokine regulation by omentin was analyzed in SC and mature adipocytes. Glucose uptake by EAT and SAT explants was determined after insulin, omentin, or combined treatment. Human vascular cells were exposed to secretomes of SC, with and without omentin treatment. Migration of smooth muscle cells and expression of adhesion molecules were determined by wound healing or real-time polymerase chain reaction, respectively. RESULTS Omentin treatment raised adipogenesis-induced adiponectin levels on SC of EAT and reduced TNF-α expression levels (0.58 ± 0.14-fold change; P = 0.034) in mature adipocytes. Omentin improved the insulin activity of EAT and SAT explants from cardiovascular disease patients. Finally, secretomes of SC under omentin treatment reduced the migration of smooth muscle cells. CONCLUSIONS Exogenous omentin might support a cardioprotective role through its effect on EAT regarding glucose uptake, anti-inflammatory response, and its paracrine role on smooth muscle cells.