Cell adhesion molecules have been implicated in the colonization of cancer cells to distant organs. Prostate cancer (PCa) has a propensity to metastasize to bone, and cadherin-11, which is an osteoblast cadherin aberrantly expressed in PCa cells derived from bone metastases, has been shown to play a role in the metastasis of PCa cells to bone. However, the mechanism by which cadherin-11 is involved in this process is not known. Here, we show that expression of cadherin-11 in cadherin-11–negative C4-2B4 cells increases their spreading and intercalation into an osteoblast layer and also stimulates C4-2B4 cell migration and invasiveness. The downregulation of cadherin-11 in cadherin-11–expressing metastatic PC3 cells decreases cell motility and invasiveness. Further, both the juxtamembrane (JMD) and β-catenin binding domains (CBS) in the cytoplasmic tail of cadherin-11 are required for cell migration and invasion, but not spreading. Gene array analyses showed that several invasion-related genes, including MMP-7 and MMP-15, are upregulated in cadherin-11–expressing, but not in cad11-ΔJMD–expressing or cad11-ΔCBS–expressing, C4-2B4 cells. These observations suggest that cadherin-11 not only provides a physical link between PCa cells and osteoblasts but also increases PCa cell motility and invasiveness that may facilitate the metastatic colonization of PCa cells in bone. Cancer Res; 70(11); 4580–9. ©2010 AACR.