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Benzoxathiolone derivatives have been reported to show pharmacological potentials in the psoriasis and acne. However, molecular basis for these pharmacological properties is little known. We postulated that the derivatives could mediate some of their pharmacological actions by modulating nuclear factor (NF)-κB activation, which is closely linked to the inflammatory and immune disorders. In this study, a novel iminobenzoxathiolone LYR-71 of 6-methyl-2-propylimino-6,7-dihydro-5 H -benzo[1,3]oxathiol-4-one has been demonstrated to inhibit in vitro catalytic activity of inhibitory κB (IκB) kinase β (IKKβ), a key enzyme required for NF-κB activation, with an IC50 value of 7 μM. LYR-71 inhibited IKKβ-mediated phosphorylation of cytoplasmic IκBα in lipopolysaccharide (LPS)-activated macrophages, and sequentially preventing IκBα degradation as well as transcriptional activation of NF-κB. Furthermore, LYR-71 down-regulated LPS-induced transcription of interleukin (IL)-1β or other cytokines in the cells, and inhibited expression vector IKKβ-elicited IL-1β promoter activity. Taken together, LYR-71 was an efficient inhibitor of IKKβ, preventing NF-κB activation in macrophages, and this mechanism of action could contribute its down-regulatory effect on LPS-induced expression of inflammatory cytokines at the transcription level.