The metabolic syndrome (MetS) is characterized by constellation of clinical and biochemical features that increase the risk of cardiovascular disease. Neuropeptide Y (NPY) is a neurotransmitter and enhances the development of obesity and other aspects of MetS. We determined the association between NPY Leu7Pro polymorphism and features of MetS in Iranian patients with coronary artery disease (CAD). A total of 550 patients with CAD including individuals with (n = 184) and without MetS (n = 366) were genotyped by polymerase chain reaction-restriction fragment length polymorphism. A significantly higher frequency of the Leu7Pro polymorphism was found in patients with MetS compared with the non-MetS patients (P = .001). Furthermore, there was a significant difference in Pro7 frequency between diabetics versus nondiabetics (P = .005), dyslipidemic versus nondyslipidemic (P = .04), and obese versus nonobese (P = .001) in this population. Leu7Pro polymorphism is associated with the MetS in patients with CAD.