Lipopolysaccharide (LPS)-stimulated RAW 264.7 cells are commonly used as a model for assessing the anti-inflammatory or chemopreventive potential of test compounds. Epimuqubilin A, a norsesterterpene peroxide isolated from marine sponge Latrunculia sp., inhibits nitric oxide production in LPS-stimulated RAW 264.7 cells (IC(50) = 7.6 µM). At both the mRNA and protein levels, cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are suppressed in a dose-dependent manner. Mitogen-activated protein kinases (MAPKs), one major upstream signaling pathway involved in the transcription of both COX-2 and iNOS, were not affected by treatment of epimuqubilin A. However, the compound blocked the phosphorylation of inhibitor κB (IκB) kinase (IKKβ), resulting in the stabilization of IκBα, and inhibition of NF-κB p65 nuclear translocation and DNA binding. Levels of phosphorylated IKKα were not affected. This is an unique mechanistic relationship that suggests epimuqubilin A warrants further exploration as a potential therapeutic agent.