Abstract α-Iso-cubebenol, a natural compound isolated from the Schisandra chinensis fruit, strongly enhances survival rate in cecal ligation and puncture (CLP) challenge-induced sepsis. Mechanistically, α-iso-cubebenol markedly reduces viable bacteria in the peritoneal fluid and peripheral blood, by increasing production of superoxide anion. α-Iso-cubebenol also significantly attenuates widespread immune cell apoptosis in a mouse CLP sepsis model, and inhibits the production of proinflammatory cytokines including interleukin-1β (IL-1β) and IL-6 in CLP mice and lipopolysaccharide-stimulated splenocytes. We also found that α-iso-cubebenol stimulated calcium increase and degranulation in human neutrophils. α-Iso-cubebenol also strongly induced neutrophil chemotaxis, which was completely blocked by a CXCR2 antagonist, SB225002. The increased survival rateby α-iso-cubebenol was also significantly attenuated by SB225002. Taken together, the results indicate that α-iso-cubebenol-induced anti-septicactivity was mediated by CXCR2, suggesting CXCR2 as an important target for theregulation of sepsis and inflammation.