Obesity is a severe disease that causes diabetes, fatty liver, hypertension, and arteriosclerosis. It involves adipocytokines such as tumor necrosis factor-α, leptin, and resistin.The hypertrophic adipocytes induce the secretion of these adipocytokines. Regulating the growth of adipose tissue is an extremely important approach to prevent these diseases. Hypertrophy of adipose tissue is closely associated with angiogenesis, wherein neovascular vessels supply nutrients.Previous studies have shown that angiogenesis inhibitors can prevent the development of obesity in mice. In this study, we report an anti-obesity therapy targeting the neovascular vessels of adipose tissue via endothelial cell (EC) vaccination. EC vaccine was prepared using EC extract antigen, which was pulsed to dendritic cells, and was administered thrice intradermally. The anti-obesity effect was evaluated in high-fat diet-fed obesity model mice. EC vaccination significantly suppressed the increase in body weight and hyperplasia of adipocytes and improved the accumulation of hepatic lipid droplets in these mice. Adipose tissue-induced vascular-targeted vaccine therapy is a potential novel approach for obesity.