Background and Purpose: GPR55 is a G protein-coupled receptor that recognizes several lipid molecules. GPR55 expression in human monocytes and its proinflammatory role lead us to investigate the role of GPR55 in monocyte adhesion and atherosclerosis development. Experimental Approach: We investigated monocyte adhesion in human THP-1 monocytes and atherosclerosis development in ApoE-/- mice by using O-1602 (a potent agonist of GPR55), CID16020046 (a specific GPR55 antagonist), and a high-fat diet-induced atherosclerosis model. Key Results: In human THP-1 monocytes, treatment with O-1602 significantly increased monocyte adhesion to human umbilical vein endothelial cells (HUVECs), and the O-1602-induced adhesion was inhibited by treatment with CID16020046. O-1602 induced the expression of Mac-1 adhesion molecules, whereas CID16020046 inhibited this induction. Analysis of the promoter region of Mac-1 elucidated the binding sites of AP-1 and NF-κB between nucleotides -750 and -503 as GPR55 responsive elements. Furthermore, O-1602 induction of Mac-1 through AP-1 and NF-B was found to be dependent on the signaling components of GPR55, that is, Gq protein, Ca2+, CaMKK, and PI3K. In an in vivo study of high-fat diet-induced atherosclerosis in ApoE-/- mice, administration of CID16020046 ameliorated atherosclerosis development. These results suggest that high-fat diet-induced GPR55 activation leads to adhesion of monocytes to endothelial cells via induction of Mac-1, and CID16020046 blockage of GPR55 could suppress monocyte adhesion to vascular endothelial cells through suppression of Mac-1 expression, leading to protection against the development of atherosclerosis. Conclusions: This report suggests that GPR55 may be a therapeutic target for atherosclerosis development.