High mobility group box-1 (HMGB1), a representative damage-associated molecular patterns (DAMPs), has been reported to be involved in many inflammatory diseases. To validate HMGB1 as a target molecule of inflammatory diseases and to examine the effects of inhibition of HMGB1 on the diseases, we raised anti-HMGB1 monoclonal antibody (mAb) neutralizing extracellular HMGB1 and characterized it. We report the effects of anti-HMGB1 mAb on brain infarction, brain hemorrhage, brain trauma, epilepsy and neuropathic pain using animal models. In these wide range of disease conditions, we found a common event; the injury-induced translocation of HMGB1 from nuclei to extracellular space, especially in neurons. Released HMGB1 disrupt the integrity of blood-brain barrier (BBB) and increased the permeability of BBB, associated with inflammatory responses including the induction of pro-inflammatory cytokines. The intravenous injection of anti-HMGB1 mAb inhibited translocation of HMGB1, BBB disruption, expression of inflammatory molecules and improved neurological symptoms of different kinds of disease models. These results as a whole indicated that HMGB1 may be a very sensitive factor which is mobilized readily by different injurious insults to the brain and that HMGB1 release may be present most upstream of cascade of events triggering BBB disruption and brain inflammation. Thus, HMGB1 may be an excellent target for the treatment of above-mentioned diseases. Anti-HMGB1 mAb provide a novel and potential therapy for these severe disease conditions.