Objective: Serum levels of nitric oxide (NO) are decreased in patients with atherosclerosis and also are a risk factor for the development of atherosclerosis. Endothelial dysfunction and diffuse atherosclerosis have been proposed for the etiology of coronary artery ectasia (CAE). The purpose of this clinical trial was to determine the relationship between CAE and serum NO levels. Methods: This prospective controlled study was conducted between January 2008 and March 2012. Serum levels of NO were compared in 40 patients with CAE (mean age 60.1±7.3 years) and 40 patients with normal coronary arteries (mean age 57.6±5 years) as a control group. CAE was diagnosed when a segment of coronary artery was more than 1.5 times the diameter of the adjacent healthy segment. Patients with stenotic atherosclerotic plaques, slow coronary flow, previous history of revascularization, acute coronary syndromes, left ventricular dysfunction, valvular heart disease, and systemic diseases were not included in the study. The effect of NO on the outcome was studied by constructing a receiver operating characteristic (ROC) curve with CAE as the primary variable. Effects of different variables on CAE were calculated using binary logistics regression analysis. Results: Serum NO concentrations were significantly lower in patients with CAE than in the control group (42.1±20.1 µmol/L vs. 77.3±15.7 µmol/L, p<0.001). According to the results of the multivariate regression analysis, LDL and NO levels were identified as independent factors associated with CAE (OR=1.02, 95% CI 1–1.04, p=0.02 and OR=0.88, 95% CI 0.83–0.93, p=0.001, respectively). ROC analysis revealed that using a cut-off point of 63.3, NO level predicts CAE with a sensitivity of 87.5% and specificity of 90%. Conclusion: Our study indicates that decreased levels of NO are present in patients with CAE compared to patients with normal coronary arteries, supporting the hypothesis that decreased levels of NO might be associated with CAE development.