Coronary artery disease (CAD) is a major health issue. This study focused on pericardial macrophages and small extracellular vesicles (sEVs) in CAD. The macrophages in CAD patients showed reduced expression of protective markers and unchanged levels of proinflammatory receptors. Similar changes were observed in buffy-coat–derived macrophages when stimulated with CAD pericardial fluid-derived sEVs. The sEV contained miRNA-6516-5p, which inhibited CD36 and affected macrophage lipid uptake. These findings indicate that sEV-mediated miRNA actions contribute to the decrease in protective pericardial macrophages in CAD.