Background. HIV-positive persons have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods. In the general population, 23 common single nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on gender and cohort. Results. A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P=2.9x10-4). In the final, multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval, 1.05-2.04). This effect was similar to hypertension (OR=1.36; 95% CI, 1.06-1.73), hypercholesterolemia (OR=1.51; 95% CI, 1.16-1.96), diabetes (OR=1.66; 95% CI, 1.10-2.49), >1 year lopinavir exposure (OR=1.36; 95% CI, 1.06-1.73) and current abacavir treatment (OR=1.56; 95% CI, 1.17-2.07). The effect of the genetic risk score was additive to the effect of non-genetic CAD risk factors, and did not change after adjustment for family history. Conclusions. In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.