Genetic alterations of 16q21-q22, the locus of a 6-cadherin cluster, are frequently involved in multiple tumors, suggesting the presence of critical tumor suppressor genes (TSGs). Using 1 Mb array comparative genomic hybridization (aCGH), we refined a small hemizygous deletion (~1 Mb) at 16q21-22.1, which contains a single gene Cadherin-11 (CDH11, OB-cadherin). CDH11 was broadly expressed in human normal adult and fetal tissues, while its silencing and promoter CpG methylation were frequently detected in tumor cell lines, but not in immortalized normal epithelial cells. Aberrant methylation was also frequently detected in multiple primary tumors. CDH11 silencing could be reversed by pharmacologic or genetic demethylation, indicating an epigenetic mechanism. Ectopic expression of CDH11 strongly suppressed tumorigenecity and induced tumor cell apoptosis. Moreover, CDH11 was found to inhibit Wnt/β-catenin and AKT/Rho A signaling, as well as actin stress fiber formation, thus further inhibiting tumor cell migration and invasion. CDH11 also inhibited epithelial-to-mesenchymal transition and downregulated stem cell markers. Thus, our work identifies CDH11 as a functional tumor suppressor and an important antagonist of Wnt/β-catenin and AKT/Rho A signaling, with frequent epigenetic inactivation in common carcinomas.