Lack of reliable prognostic markers hinders accurate prediction of disease progression in prostate cancer. The inducible proinflammatory enzyme cyclooxygenase-2 (COX-2) is implicated in prostate carcinogenesis, but its role in cancer progression is less clear. We examined whether COX-2 expression evaluated by immunohistochemistry (IHC) in radical prostatectomy (RP) specimens can predict biochemical recurrence. Archival prostate cancer specimens (n 5 60) were obtained from patients who underwent RP, but had not received neoadjuvant hormonal therapy. Twentythree patients had biochemical or clinical recurrence (mean time of recurrence: 38.2 months), and 37 patients were recurrence free (mean follow-up: 95 months). COX-2 expression was determined by IHC, using an anti-COX-2 antibody. Three individuals scored the staining independently, as high-or low-expression. COX-2 was expressed in prostate cancer cells, in adjacent normal glands and in specimens from patients who later progressed. At 62-months follow-up, COX-2 staining predicted progression with 82.4% sensitivity and 81.3% specificity. Sensitivity (86.4%) and specificity (86.7%) improved at 100-months follow-up. In univariate analysis, Gleason score, preoperative PSA, extraprostatic extension, margin, seminal vesicle invasion, and high COX-2 expression were significant predictors of biochemical recurrence (p < 0.05). In multivariate analysis, preoperative PSA (hazard ratio/unit PSA change 1.080; p 5 0.0036) and COX-2 expression (hazard ratio 16.442; p < 0.0001) were independent prognostic indicators. Patients with PSA > 7 ng/ml and high COX-2 expression had the highest probability of recurrence (Kaplan-Meier analysis). COX-2 expression is an independent predictor of prostate cancer progression following RP and underscores the significance of inflammatory factors in this process. ' 2006 Wiley-Liss, Inc.Key words: inflammation; immunohistochemistry; PSA; cancer progression; prognostic indicators; multivariate analysis; tumor markers Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) are prostaglandin endoperoxide synthases, which are rate limiting enzymes in the conversion of the fatty acid arachidonic acid into physiologically active eicosanoids such as prostaglandin, thromboxane and prostacyclin. 1 COX-2 is the inducible form of COX that is frequently elevated in cancer tissues. [2][3][4] Although the mechanism of COX-2 action in carcinogenesis or progression is not well established, COX-2 inhibitors have been shown to be chemopreventive in cancer, specifically in colorectal cancer. [5][6][7] The expression and role of COX-2 in prostate cancer has been a topic of several reports over the decade. 8,9 There exists some controversy over the expression, detection and the putative role of COX-2 in prostate carcinogenesis and progression. While early studies reported high-level expression of COX-2 in prostate, findings from subsequent studies have been mixed. [10][11][12] Typically, later studies reported low or no expression in normal, benign prostatic hyperplasi...