INTRODUCTION: Endogenous cannabinoid compounds are involved in many physiological processes, including bone metabolism. Cannabinoid receptor 2 (CB2) plays a role in modulating bone density, but published research results are conflicting. Furthermore, the specific role of CB2 in inflammation-induced bone resorption and craniofacial bone density has not been reported. The objective of this study was to assess the role of CB2 in dental pulp exposure-induced periapical bone loss and mandibular bone density. METHODS: Adult female wild-type (WT) and CB2 homozygous knockout (KO) mice were used. Pulp exposures were created unilaterally in the mandibular first molars, and the pulp was left exposed to the oral cavity to induce periapical lesion formation. Mandibles were harvested 26 days after pulp exposure. Mandibular bone mineral density and periapical lesion volume were assessed using micro-computed tomographic imaging. RESULTS: Periapical lesion volume measured on the mesial root of the pulp-exposed first molar was significantly less in CB2 KO than WT mice (P <.05). No significant difference was detected between KO and WT mice in the size of the PDL space measured on the mesial root of the contralateral intact first molar. CB2 KO mice exhibited greater mandibular bone density than WT mice (P <.05). CONCLUSIONS: CB2 plays a role in mandibular bone metabolism. Increased bone density in CB2 KO mice may contribute to the smaller periapical lesion size observed after pulp exposure in KO compared with WT mice. Additional experiments are needed to further elucidate the function of CB2 and clinical implications of cannabinoids on bone and periapical pathosis.