Recruitment of leukocytes to inflammatory sites is crucial in the pathogenesis of chronic inflammatory diseases. The aim of this study was to investigate if activation of CB₂ cannabinoid receptors would modulate the chemotactic response of human monocytes. Human monocytes treated with the CB₂ agonist JWH-015 for 12–18 h showed significantly reduced migration to chemokines CCL2 and CCL3, associated with reduced mRNA and surface expression of their receptors CCR2 and CCR1. The induction of ICAM-1 in response to IFN-γ was inhibited by JWH-015. Moreover, JWH-015 cross-desensitized human monocytes for migration in response to CCL2 and CCL3 by its own chemoattractant properties. The CB₂-selective antagonist SR-144528, but not the CB₁ antagonist SR-147778, reversed JWH-015-induced actions, whereas the CB₂ agonist JWH-133 mimicked the effects of JWH-015. The investigation of underlying pathways revealed the involvement of phosphatidylinositol 3-kinase/Akt and ERK1/2 but not p38 MAPK. In conclusion, selective activation of CB₂ receptors modulates chemotaxis of human monocytes, which might have crucial effects in chronic inflammatory disorders such as atherosclerosis or rheumatoid arthritis.