Objectives The purpose of this study was to determine whether smoking cessation improves flow-mediated dilation (FMD) of the brachial artery. Background The long-term effects of continued smoking and smoking cessation on endothelial function have not been described previously. Methods This was a 1-year, prospective, double-blind, randomized, placebo-controlled clinical trial of the effects of 5 smoking cessation pharmacotherapies. FMD was measured by B-mode ultrasonography before and 1 year after the target smoking cessation date. Cessation was verified by exhaled carbon monoxide levels. Delta FMD was compared among study arms and between subjects who successfully quit smoking and those who continued to smoke. Predictors of baseline FMD and Delta FMD were identified by multivariable regression. Results The 1,504 current smokers (58% female, 84% white) were 44.7 +/- 11.1 years of age and smoked 21.4 +/- 8.9 cigarettes/day. Baseline FMD was similar in each treatment arm (p = 0.499) and was predicted by BA diameter (p < 0.001), reactive hyperemia blood flow (p < 0.001), high-density lipoprotein cholesterol (p = 0.001), and carbon monoxide (p = 0.012) levels. After 1 year, 36.2% quit smoking. FMD increased by 1% (6.2 +/- 4.4% to 7.2 +/- 4.2%) after 1 year (p = 0.005) in those who quit, but did not change (p = 0.643) in those who continued to smoke. Improved FMD among quitters remained significant (p = 0.010) after controlling for changes in brachial artery diameter, reactive hyperemia, low-density lipoprotein cholesterol, and the presence of a home smoking ban. Conclusions Despite weight gain, smoking cessation leads to prolonged improvements in endothelial function, which may mediate part of the reduced cardiovascular disease risk observed after smoking cessation. (Smoking Cessation Medications: Efficacy, Mechanisms and Algorithms; NCT00332644) (J Am Coll Cardiol 2010;55:1988-95) (C) 2010 by the American College of Cardiology Foundation