Numerous evidences indicated that angiogenesis was a crucial step in the development of tumor, thus the immunotherapy of antiangiogenesis has been involved as potentially relevant candidate targets of cancer immunotherapy. Recently, tumor endothelial marker 8 (TEM8) was discovered to be dominantly expressed in tumor endothelium, which presented a new strategy to antiangiogenesis therapy. However, up to date, the related study of TEM8 on antiangiogenesis is very few. In this study, we constructed a xenogenic DNA vaccine encoding human TEM8 carried by attenuated Salmonella typhimurium. The results demonstrated that oral administration of this xenogenic vaccine overcame peripheral immune tolerance and generated TEM8-specific CD8+ cytotoxic T-cell response. Moreover, this vaccine effectively protected mice from lethal challenges against tumor cells, reducing tumor growth, and increasing the mice life span. In addition, angiogenesis in the tumors was suppressed without obvious side effect. These results indicated that DNA vaccine encoding xenogenic TEM8 might act as a potential strategy for antiangiogenesis immunotherapy of tumors.