Angiogenesis is a rate-limiting step in the development of tumors. Here, we demonstrate that oral minigene DNA vaccines against murine vascular endothelial growth factor receptor-2 (FLK-1), a self-antigen overexpressed on proliferating endothelial cells in the tumor vasculature, induced protection against tumors of different origin in syngeneic BALB/c mice. This protection is mediated by CD8 T cells, which specifically kill FLK-1(+) endothelial cells, resulting in marked suppression of tumor angiogenesis. More importantly, the minigene vaccine proved to be of similar efficacy as a vaccine encoding the whole FLK-1 gene. These data suggest a FLK-1 minigene vaccine provides a more flexible alternative to the whole gene vaccine and will facilitate their future design and clinical applications in cancer therapy and prevention.