Background: Neuropeptide Y (NPY), a 36 amino acid peptide, has several effects on cardiovascular system. It is demonstrated that the angiogenic activity of NPY is similar to fibroblast growth factor and vascular endothelial growth factor (VEGF). The aim of this study was to evaluate the effect of systemic administration of antagonist of NPY receptor (BIIE0742) on coronary angiogenesis in normal and diet-induced obese animals. Materials and Methods: Twenty-four male mice were received high-fat diet (HFD) or normal diet (ND) for 14 weeks. Then, each group was randomized to the treatment of antagonist of NPY receptor (BIIE0246) or saline as following: ND+ BIIE0246 (100 μl/kg; i.p.), ND+ saline, HFD+ BIIE0246, HFD+ saline. After 14 days, blood samples were taken, and myocardial tissue (left ventricle) from all experimental groups was evaluated by immunohistochemistry. Results: Serum VEGF concentration and VEGF: Soluble VEGF receptor (sVEGFR)-1 ratio in obese animals was higher than normal group. Administration of BIIE0246 significantly reduced serum VEGF and VEGF: sVEGFR-1 ratio and increased serum sVEGFR-1 concentrations in obese animals (P < 0.05). In normal animals, BIIE0246 increased serum sVEGFR-1 level and decreased VEGF: sVEGFR-1 ratio. Serum nitrite did not alter after administration of BIIE0246 in both groups (P > 0.05). Myocardial capillary density expressed as the number of CD31 positive cells/mm2 was reduced after NPY antagonist treatment in obese and normal animals (P > 0.05). Conclusion: Administration of NPY antagonist impairs myocardial capillary density, reduces angiogenic factors and elevates anti-angiogenic factors, and there are no differences between obese and normal animals.