Long-term use of cocaine (⩾15 years) and antiretroviral therapy (ART) have been implicated in cardiovascular complications. Nevertheless, the individual and combined effects of ART and cocaine use on silent coronary artery disease have not been fully investigated.Methods: Computed tomography coronary angiography was performed for 165 human immunodeficiency virus (HIV)– infected African American study participants aged 25–54 years in Baltimore, Maryland, with contrast-enhanced 64-slice multidetector computed tomography imaging.Result: Significant (⩾50%) coronary stenosis was detected in 24 (15%) of 165 participants. The prevalence of significant stenosis among those who had used cocaine for ⩾15 years and had received ART for ⩾6 months was 42%. Exact logistic regression analysis revealed that long-term cocaine use(adjusted odds ratio, 7.75; 95% confidence interval, 2.26–31.2) and exposure to ART for ⩾6 months(adjusted odds ratio, 4.35; 95% confidence interval, 1.30–16.4) were independently associated with the presence of significant coronary stenosis. In addition, after controlling for confounding factors,both stavudine use for ⩾6 months or combivir use for ⩾6 months were independently associated with the presence of significant coronary stenosis.Conclusions: Long-term exposure to ART may be associated with silent coronary artery disease;however, the magnitude of increased risk associated with ART was much lower than the risk associated with cocaine use or traditional risk factors. Cardiovascular monitoring and aggressive modification of cardiovascular risk factors are essential for reducing the risk of coronary artery disease in HIV-infected individuals. Extensive efforts should also be made to develop effective cocaine use cessation programs for HIV-infected cocaine users.