BACKGROUND: Single polymorphisms of different genes have been associated with coronary artery disease (CAD). The aim of this study was to evaluate the benefit of analyzing multiple genetic polymorphisms as a compound unit to assess the individual genetic burden for CAD. METHODS AND RESULTS: The study population consisted of 100 case patients with, and 100 control patients without, angiographically proven CAD. The patients were matched for age, sex, and numbers of standard cardiac risk factors. Sixteen different genetic polymorphisms were analyzed using polymerase chain reaction-based technologies. None of these polymorphisms showed a significant difference in the allele frequency between case and control patients. Eight genes with a higher allele frequency in the case group (delta allele frequency >0.05) were defined as risk alleles (RA) and subsequently tested as a compound unit. A risk stratification for 64.5% of all patients was possible when eight genes with their 16 RA were included in the analysis. With more than eight RA per individual, the odds ratio for developing CAD was 3.21 (95% CI 1.77-5.82, P<0.001). However, there was still an overlap in the number of RA in case and control patients. A computer simulation estimated that more than 200 polymorphisms were needed for a reasonable genetic discrimination for patients at risk for CAD. CONCLUSIONS: An increasing number of risk alleles are associated with an elevated risk for CAD. An analysis of multiple polymorphisms, some several hundred, each with a small impact, may allow improved assessment of the individual genetic burden for CAD. Larger studies are needed to prove this hypothesis.