The immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Unregulated activities of these mediators can lead to the development of various inflammatory diseases. A variety of safe and effective anti-inflammatory agents are available with many more drugs under development. Of the natural compounds, the sesquiterpenes (nootkatone, ${alpha}$-cyperone, valencene and ${alpha}$-selinene) isolated from C. rotundus L. have received much attention because of their potential antiinflammatory effects. However, limited studies have been reported regarding the influence of sesquiterpene structure on anti-inflammatory activity. In the present study, the anti-inflammatory potential of four structurally divergent sesquiterpenes was evaluated in lipopolysaccaride (LPS)-stimulated RAW 264.7 cells, murine macrophages. Among the four sesquiterpenes, ${alpha}$-cyperone and nootkatone, showed stronger anti-inflammatory and a potent NF-${kappa}B$ inhibitory effect on LPS-stimulated RAW 264.7 cells. Molecular analysis revealed that various inflammatory enzymes (iNOS and COX-2) were reduced significantly and this correlated with downregulation of the NF-${kappa}B$ signaling pathway. Additionally, electrophoretic mobility shift assays (EMSA) elucidated that nootkatone and ${alpha}$-cyperone dramatically suppressed LPS-induced NF-${kappa}B$-DNA binding activity using 32Plabeled NF-${kappa}B$ probe. Hence, our data suggest that ${alpha}$-cyperone and nootkatone are potential therapeutic agents for inflammatory diseases.