ARTICLE ABSTRACTEpithelial ovarian carcinoma (EOC) is a deadly disease, and little is known about the mechanisms underlying its metastatic progression. Using human specimens and established cell lines, we determined that the G-protein–coupled seven-transmembrane fractalkine receptor (CX3CR1) is expressed in primary and metastatic ovarian carcinoma cells. Ovarian carcinoma cells robustly migrated toward CX3CL1, a specific ligand of CX3CR1, in a CX3CR1-dependent manner. Silencing of CX3CR1 reduced migration toward human ovarian carcinoma ascites fluid by approximately 70%. Importantly, adhesion of ovarian carcinoma cells to human peritoneal mesothelial cells was dependent on CX3CL1/CX3CR1 signaling. In addition, CX3CL1 was able to induce cellular proliferation. Together, our data suggest that the fractalkine network may function as a major contributor to the progression of EOC, and further attention to its role in the metastasis of this deadly malignancy is warranted. Mol Cancer Res; 10(1); 11–24. ©2011 AACR.