The two naphthopyrones 6-methoxycomaparvin (1) and 6-methoxycomaparvin 5-methyl ether (2) were isolated from a bioactive methanol-soluble extract of the Fijian echinoderm Comanthus parvicirrus. Their structures were assigned on the basis of spectroscopic methods. X-ray diffraction analysis was used to confirm the structure of 1. Both compounds were tested for their potential to inhibit the activation of the transcription factor NF-kappaB, which plays an important role in cancer development and inflammation, and the mechanism of action of the two compounds was investigated. Both naphthopyrones 1 and 2 completely inhibit TNF-alpha-induced NF-kappaB activation at a concentration of 300 microM by inhibiting the enzymatic activity of the kinase IKKbeta.