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Objectives: To examine the immunohistochemical expression of cyclooxygenase-2 (COX-2) and nuclear factor-κB (NF-κB) in benign endometrial polyps (EPs), endometrial hyperplasia (EH), endometrial intraepithelial neoplasia (EIN), and endometrioid endometrial cancer (EC). Methods: The immunohistochemical expression of COX-2 and NF-κB was performed using an Aperio Scanscope XT automated system in 218 patients with endometrioid EC and 107 patients with nonmalignant endometrial lesions: 53 with benign EPs, 37 with EH, and 17 with EIN. Results: COX-2 and NF-κB p50 expression were significantly lower in EC compared with nonmalignant lesions. We observed significant decreased NF-κB p65 expression in EC vs EPs (P < .001) and EH (P = .014) as well as in EIN vs EPs (P = .01). For patients with EC, COX-2 correlated positively with NF-κB p65 and NF-κB p50 (P < .001). Grade 3 tumors had a higher mean expression of NF-κB p65 (P = .03). NF-κB p50, NF-κB p65, and COX-2 expression had no impact on survival. Conclusions: We conclude that COX-2 and NF-κB expression are lower in EC compared with nonmalignant endometrial lesions. COX-2 and NF-κB expression have no prognostic value in EC. [ABSTRACT FROM AUTHOR]