Interleukin-20 (IL-20) is a proinflammatory cytokine involved in rheumatoid arthritis, atherosclerosis, and osteoporosis. However, little is known about the role of IL-20 in oral cancer. We explored the function of IL-20 in the tumor progression of oral cancer. IL-20 expression levels in tumorous and nontumorous oral tissue specimens from 40 patients with four different stages oral cancer were analyzed with immunohistochemistry (IHC) staining and quantitative real-time PCR (qRT-PCR). Expression of IL-20 and its receptor subunits was higher in clinical oral tumor tissue than in nontumorous oral tissue. The role of IL-20 was examined in two oral cancer cell lines (OC-3 and OEC-M1). In vitro, IL-20 promoted TNF-α, IL-1β, MCP-1, CCR4, and CXCR4 and increased proliferation, migration, reactive oxygen species (ROS) production, and colony formation of oral cancer cells via activated STAT3 and AKT/JNK/ERK signals. To evaluate the therapeutic potential of anti–IL-20 monoclonal antibody 7E for treating oral cancer, an ex vivo tumor growth model was used. In vivo, 7E reduced tumor growth and inflammation in oral cancer cells. In conclusion, IL-20 promoted oral tumor growth, migration, and tumor-associated inflammation. Therefore, IL-20 may be a novel target for treating oral cancer, and anti–IL-20 monoclonal antibody 7E may be a feasible therapeutic. Mol Cancer Res; 10(11); 1430–9. ©2012 AACR.