The aim of the study was to assess whether long-term antiretroviral therapy (ART) is associated with the risk of coronary plaques in HIV-infected cardiovascularly asymptomatic African Americans. Between August 2003 and December 2007, 176 HIV-infected cardiovascularly asymptomatic African Americans were consecutively enrolled in an observational study investigating the effects of ART on subclinical atherosclerosis in Baltimore, Maryland. Computed tomography coronary angiography was performed to detect coronary plaques. The overall prevalence rate of coronary plaques was 30%. After adjusting for gender, total cholesterol, and cocaine use, logistic regression analysis revealed that exposure to ART for more than 18 months (adjusted odds ratio [OR]: 2.20, 95% confidence interval [CI]: 1.01, 4.79) was independently associated with the presence of coronary plaques. A higher HIV viral load was univariately associated with the presence of noncalcified plaques. Use of ART (>18 months) was independently associated with the presence of noncalcified plaques (adjusted OR: 7.61, 95% CI: 1.67, 34.7), whereas cocaine use (>15 years) was independently associated with the presence of calcified plaques (adjusted OR: 2.51, 95% CI: 1.11, 5.67). This study suggests that long-term exposure to ART may be associated with coronary plaques. Because long-term use of ART and HIV replication may be associated with the presence of noncalcified plaques, some of which may be more vulnerable to rupture, an intensive lifestyle intervention to reduce traditional risk factors for coronary artery disease (CAD) is ultimately vital to those who are on ART. This study also suggests that cocaine cessation is the single most effective strategy to prevent CAD in HIV-infected cocaine users.