Technical Abstract: Background: Few studies have examined the usefulness of genetic scores to identify subjects at increased risk for coronary heart disease (CHD). Using a genetic predisposition score (GPS), integrating the additive associations of a set of single nucleotide polymorphisms (SNPs) with CHD, we examined the consequences of the joint presence of a high GPS and conventional risk factors (CRFs). Methods: We studied eleven SNPs at eight loci in 197 participants with prior CHD and 524 CHD-free subjects from the Boston Puerto Rican Health Study. Each polymorphism contributed 1 unit (high-risk allele homozygous), 0.5 unit (heterozygous) and 0 units (low-risk allele homozygous) to the GPS. Odds ratio (OR) of CHD for those at high-risk defined by a GPS (>5) and simultaneous presence of an established CHD risk factor were estimated and compared with subjects at low-risk, for both the GPS and each non-genetic CHD risk factor. Results: The mean score was higher in participants with prior CHD than those CHD-free (P=0.015), and the multivariate OR for CHD with a score >5 was 2.90 (1.70-4.99; P<0.001). Joint presence of a high GPS and each CRF was associated with a significantly increased risk of CHD. Comparing participants with low GPS (</=5) to those with high GPS (reference value), the OR was 0.44(0.21-0.89) for ever smokers, 0.43(0.24-0.79) for ever drinkers, 0.35(0.17-0.71) for low physical activity, 0.52(0.28-0.96) for hypertension, and 0.34(0.14-0.81) for dyslipidemia. Conclusions: A simple genetic score integrating the additive impact of eleven polymorphisms may identify those subjects at increased risk of CHD beyond conventional risk factors.