Aims: Recent evidence indicates that the defective ability to clear apoptotic cells by macrophages (efferocytosis) and the resultant apoptotic cells accumulation in atherosclerotic plaques play an important role during the progression of unstable plaques. The cannabinoid type 2 receptor (CB2), has recently been emerging as a new target to reduce vulnerability and promote stability of plaques, however, the underlying mechanisms have not been studied in detail. In the present study, we investigated whether selective activation of CB2 improves efferocytosis of macrophages. Main methods: RAW264.7 macrophage line and primary-isolated peritoneal lavage macrophages from C57bI/6J mice were cultured. The efferocytosis of macrophages was analyzed by using flow cytometry or confocal microscopy; and the possible mechanisms involved in regulation of efferocytosis were also explored by using molecular biology methods. Key findings: We found that JWH-133 and HU-308, selective agonists of CB2 receptor, concentration-dependently increased the phagocytosis of apoptotic cells in normal-cultured and oxidative low density lipoprotein (OxLDL) - loaded RAW264.7 and primary macrophages. JWH-133 and HU-308 also up-regulated expressions of tyrosine kinase family phagocytic receptors MerTK, Tyro3 and Axl, reduced levels of TNF-alpha and reactive oxygen species (ROS) induced by OxLDL, and inhibited activation of RhoA GTPase. Significance: The selective activation of CB2 improves efferosytosis of normal-cultured and OxLDL-loaded macrophages, which might provide a novel mechanism on how CB2 activation reduces vulnerability and promotes stability of atherosclerotic plaques. (C) 2016 Elsevier Inc All rights reserved.