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The objective of this study was to compare the immunohistochemical profile and clinical course of primary peritoneal serous carcinoma (PPC) and primary ovarian serous carcinoma (OSC). These entities are virtually indistinguishable morphologically, but their differential molecular and clinical features are incompletely characterized. Twenty-nine cases of high-grade, high-stage PPC and 96 cases of stage matched OSCs were compared. PPC was identified based on the criteria proposed by the Gynecologic Oncology Group. The tumors were staged according to International Federation of Gynecology and Obstetrics criteria for ovarian cancer and graded according to World Health Organization criteria. Expression of Cox-2, CD-34, bcl-2, and p53 was compared in the two tumors and correlated with clinical data including stage, age, race, and overall survival. Although the median survival, using Kaplan-Meier test, of patients with OSC (1060 days, 35.3 months) was longer than those with PPC (708 days, 23.6 months) the difference was not statistically significant. However, Cox-2 expression was correlated with microvessel density in PPC (p=0.026) and OSC cases (p=0.005), and high expression of Cox-2 correlated with lower survival rate in OSC cases (p=0.045) but not in PPC cases (p=0.12). These findings, coupled with the morphologic overlap existing between OSC and PPC, support the view that they represent related pathologic entities.