Cocaine users represent an emergency department (ED) population that has been shown to be at increased risk for acute coronary syndrome (ACS); however, there is controversy about whether this higher risk is mediated through advanced atherosclerosis. Thus, we aimed to determine whether history of cocaine use is associated with ACS and coronary artery disease. In this matched cohort study, we selected patients with a history of cocaine use and age- and gender-matched controls from a large cohort of consecutive patients who presented with acute chest pain to the ED. Coronary atherosclerotic plaque as detected by 64-slice coronary computed tomography was compared between the groups. Among 412 patients, 44 had a history of cocaine use (9%) and were matched to 132 controls (mean age 46 +/- 6 years, 86% men). History of cocaine use was associated with a sixfold higher risk for ACS (odds ratio 5.79, 95% confidence interval 1.24 to 27.02, p = 0.02), but was not associated with a higher prevalence of any plaque, calcified plaque, or noncalcified plaque (all p>0.58) or the presence of significant stenosis (p = 0.09). History of cocaine use was also not associated with the extent of any, calcified, or noncalcified plaque (all p>0.12). These associations persisted after adjustment for other cardiovascular risk factors. In conclusion, in patients presenting to the emergency department with acute chest pain, history of cocaine use is associated with an increase in risk for ACS; however, this was not attributable to a higher presence or extent of coronary atherosclerotic plaque.