BACKGROUND: Recent work has suggested a role for nuclear factor κB (NF-κB) in the propagation of ovarian cancer cell lines, but the significance and mechanism of NF-κB in ovarian cancer is unknown. The authors hypothesized that the NF-κB pathway is over activated in aggressive ovarian cancers. METHODS: The levels of 3 NF-κB transcription factors, the activating inhibitors of NF-κB (IκB) kinases, and the NF-κB target matrix metalloproteinase 9 (MMP9) were assessed by immunohistochemistry in specimens of ovarian cancer that were obtained at diagnosis from a cohort of 33 patients who subsequently received combined paclitaxel, cisplatin, and cyclophosphamide. Associations were made between NF-κB pathway proteins and outcome. The validation of coexpression was performed at the gene level in 2 independently collected cohorts of 185 and 153 ovarian cancers. RESULTS: The presence of NF-κB proteins in newly diagnosed advanced ovarian cancers was established, and a potential association with overall survival was identified. Transcription factors p65 and v-rel reticuloendotheliosis viral oncogene homolog B (RelB) were coexpressed with IκB kinase α, 1 component of a key trimolecular regulatory complex. Coexpression of the NF-κB machinery suggested activity of NF-κB signaling in these ovarian tumors. A significant association of p50 with poor overall survival was observed (P = .02). MMP9 expression had the opposite association, in which patients who had tumors without MMP9 staining had the poorest prognosis (P = .01), and this association held true at the gene expression level in an independently collected cohort of 185 ovarian cancers. CONCLUSIONS: The deregulation of NF-κB activity may influence outcome in women who receive standard therapy for advanced ovarian cancer. Modification of the NF-κB pathway may present an opportunity to improve outcome in the subset of women who have pathway activity. © 2010 American Cancer Society.