The ubiquitous nuclear protein, high mobility group box-1 (HMGB1) functions as a late mediator of sepsis. A new rarely occurring C-methylrotenoid, named boeravinone X (comp 1), was isolated and identified from Abronia nana suspension cultures during our continuous works on the discovery of anti-septic natural products. Here, we investigated the antiseptic effects and underlying mechanisms of comp 1 against HMGB1-mediated septic responses. According to the results, comp 1 effectively inhibited lipopolysaccharide (LPS)-induced release of HMGB1, and suppressed HMGB1-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. And, comp 1 suppressed the production of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), and the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) by HMGB1. Collectively, these results indicate that comp 1 could be potential therapeutic agents for the treatment of various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.