High mobility group box 1 (HMGB1) protein is a crucial nuclear cytokine that mediates inflammatory responses, whereas persicarin is an active compound from Oenanthe javanica that has been widely researched for its neuroprotective and antioxidant activities. However, little is known of the effects of persicarin on HMGB1-mediated inflammatory response. Here, we investigated this issue by monitoring the effects of persicarin on the lipopolysaccharide (LPS) and on the cecal ligation and puncture (CLP)-mediated releases of HMGB1 and the effects of persicarin on the HMGB1-mediated modulation of inflammatory response. Persicarin potently inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells, and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. Furthermore, persicarin reduced CLP-induced HMGB1 release and sepsis-related mortality. Given these results, persicarin should be viewed as a candidate therapeutic for the treatment of severe vascular inflammatory diseases, such as, sepsis or septic shock. J. Cell. Physiol. 228: 696–703, 2013. © 2012 Wiley Periodicals, Inc.