Ischemia-reperfusion (I/R) injury continues to be a major complication of surgery and organ transplantation. In the case of liver, I/R triggers pro-inflammatory innate immune cascade and hepatic necrosis, leading to organ damage, dysfunction and ultimately poor outcome. Cannabinoid CB2 receptors are mainly expressed in cells of immunological origins and certain natural and synthetic cannabinoid CB2 ligands have been shown to modulate inflammation and attenuate I/R injury. We have investigated the effects of a novel CB2 receptor agonist on liver injury using the well-established mouse model of segmental hepatic I/R. D8 –Tetrahydrocannabivarin (D8 -THCV) is a synthetic analogue of the plant cannabinoid D9 -tetrahydrocannabivarin, and activates CB2 receptors in vitro, without affecting the activity of enzymes involved in endocannabinoid synthesis and hydrolysis. Given before ischemia, D8 -THCV significantly attenuated levels of I/R-induced hepatic pro-inflammatory cytokines and chemokines (CCL3 and CXCL2, TNF-a, ICAM-1), neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of D8 -THCV also persisted when given at the beginning of the reperfusion or 60 min after the ischemic episode. Thus, D8 -THCV activated CB2 receptors in vitro, and decreased tissue injury and inflammation associated with I/R partly via CB2 receptor activation. CB2 receptor agonists may represent a novel protective strategy against I/R injury by attenuating oxidative stress, acute and chronic inflammatory response, and cell death.