Neuropeptide-Y (NPY) is widely distributed centrally and peripherally and plays an important role in regulating glucose metabolism, energy metabolism and vascular function. Several studies had found that NPY is involved in the pathophysiology of type-2 diabetes Mellitus (T2DM). The aim of this study was to evaluate the association of NPY -399 (T/C) gene polymorphism and its serum level with susceptibility to T2DM. Seventy diabetic patients and seventy age and gender matched healthy controls were enrolled in this study. Serum NPY was measured by ELISA and NPY rs16147(-399 T/C) polymorphism was analyzed using the TaqMan allelic discrimination assay technique. Results showed significant statistical differences between the two studied groups regarding serum NPY level and NPY rs16147 (-399T/C) genotype distribution with increased serum NPY level and increased frequency of the CC and TC genotype in patients with diabetes mellitus. Conclusion: CC genotypes of NPY (-399 T/C) gene polymorphism and its associated high serum NPY level might be a genetic risk factor for T2DM.