The chemotactic response of murine peritoneal macrophages to RANTES/CCL5 was inhibited significantly following pretreatment with delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana. Significant inhibition of this chemokine directed migratory response was obtained also when the full cannabinoid agonist CP55940 was used. The CB₂ receptor-selective ligand O-2137 exerted a robust inhibition of chemotaxis while the CB₁ receptor-selective ligand ACEA had a minimal effect. The THC-mediated inhibition was reversed by the CB₂ receptor-specific antagonist SR144528 but not by the CB₁ receptor-specific antagonist SR141716A. In addition, THC treatment had a minimal effect on the chemotactic response of peritoneal macrophages from CB₂ knockout mice. Collectively, these results suggest that cannabinoids act through the CB₂ receptor to transdeactivate migratory responsiveness to RANTES/CCL5. Furthermore, the results suggest that the CB₂ receptor may be a constituent element of a network of G protein-coupled receptor signal transductional systems, inclusive of chemokine receptors, that act coordinately to modulate macrophage migration.