The presence and function of cannabinoid CB(2) receptors in the brain have been subject to debate. We report here that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB(2) receptor agonist, dose-dependently inhibits intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens dopamine (DA) in wild-type (WT) and CB(1) receptor-knockout (CB(1)(−/−)), but not CB(2)(−/−), mice. This inhibition is mimicked by GW405833, another CB(2) receptor agonist with a different chemical structure, and is blocked by AM630, a selective CB(2) receptor antagonist. Intra-accumbens JWH133 alone dose-dependently decreases, while intra-accumbens AM630 elevates, extracellular DA and locomotion in WT and CB(1)(−/−) mice, but not in CB(2)(−/−) mice. Intra-accumbens AM630 also blocks the reduction in cocaine self-administration and extracellular DA produced by systemic administration of JWH133. These findings, for the first time, suggest that brain CB(2) receptors modulate cocaine’s rewarding and locomotor-stimulating effects, likely by a DA-dependent mechanism.