Vascular endothelial growth factor receptor 2 (VEGFR2/KDR) plays a crucial role in tumor-associated angiogenesis and vascularization. It has been established that monoclonal antibodies against VEGFR2 can inhibit angiogenesis. In this study, two naturally processed CD8 T-cell epitopes (VILTNPISM and FSNSTNDILI) were identified from murine KDR. Cytotoxic T lymphocytes targeting endothelial cells could be directly monitored by KDR2 and KDR3 Elispots or major histocompatibility complex class I tetramer staining. Immunization with these two peptides effectively reduced angiogenesis and inhibited tumor growth in mouse models. Thus, vaccination with KDR peptides alone or in combination with other anti-angiogenesis agents may afford a novel immunotherapy for inhibition of tumor growth.