The transcription factor nuclear factor kappa B (NF-κB) plays a crucial role in the regulation of the inflammatory response and contributes to the development of various diseases (1). Thus, its inhibition is considered a promising approach to combat inflammation (2). In this study, we applied a bioactivity-guided approach to identify NF-κB inhibitors from the stem bark of Himatanthus sucuuba, an Amazonian plant traditionally used to treat inflammation-related disorders. We identified the spirolactone iridoid plumericin as a potent NF-κB inhibitor. Plumericin inhibits NF-κB activation in TNF-α stimulated HEK293 cells stably transfected with a NF-kB-driven luciferase reporter gene (293/NF-κB-luc cells), suppresses TNF-α-induced surface expression of adhesion molecules ICAM-1, VCAM-1 and E-selectin in endothelial cells, and reduces neutrophil recruitment in thioglycollate-induced peritonitis in mice. The effect of plumericin on the NF-κB signalling reveals to be a direct inhibition of the upstream kinase IKK-β. Consequently, it abolishes TNF-α-induced IκB phosphorylation and subsequent degradation. These findings might contribute to the development of promising anti-inflammatory leads and provide scientific evidence for the traditional use of Himatanthus sucuuba against inflammatory diseases.