OBJECTIVES: Chemokine CXCL12 and its unique receptor CXCR4 have been recently implicated in cancer metastasis. Our goal was to explore expression of CXCL12 and CXCR4 protein in normal ovarian surface epithelium, primary tumors and paired metastases of epithelial ovarian cancer as well as its association with clinicopathological features. We also wanted to test if expression of CXCR4 has prognostic value in epithelial ovarian cancer patients. METHOD: Sections from 6 normal ovarian surface epithelium, 44 primary epithelial ovarian tumors and 30 paired metastatic tumors in omentum were evaluated for CXCL12 and CXCR4 expression using immunohistochemistry (IHC). RESULTS: All samples of normal ovarian surface epithelium were negative for CXCL12 and CXCR4 protein. Ovarian cancer cells mainly showed cytoplasmic staining of CXCL12 and CXCR4. CXCL12 and CXCR4 staining were detected in 40/44 (91%) and 26/44 (59%) patients with primary epithelial ovarian tumors respectively. CXCR4 expression in primary tumors had no significant correlation with lymph nodes metastasis. However, if we combined CXCR4 expression in primary tumors with metastatic tumors, a significant correlation with lymph nodes metastasis was found (P = 0.018). The intensity of CXCL12 staining correlated with ascites (P = 0.014). The rate of CXCR4 expression in refractory and recurrent group (81% versus 28%, P = 0.0008) was significantly higher than that in no-recurrent group. After a median follow-up of 37 months, CXCR4 expression was found associated with an unfavorable prognosis with significantly reduced median disease progression-free survival and overall survival of 15 and 27 months (P = 0.0004, P = 0.017) respectively. Median time-to-event was not reached in patients with negative CXCR4 staining. In multivariate analysis, CXCR4 expression and residual tumor size emerged as independent prognostic factors in epithelial ovarian cancer patients. CONCLUSIONS: This article provides the first evidence that CXCR4 expression could be an independent prognostic factor for epithelial ovarian cancer patients.