Abstract —In polygenetic disorders, such as ischemic heart disease, the investigation of gene-gene interactions rather than determination of single gene effects is crucial to better understand the contribution of genetic factors. The 825T allele of the G-protein β 3 -subunit gene ( GNB3 ) associated with enhanced G-protein signaling is a candidate to interact with the angiotensin-converting enzyme ( ACE ) deletion/insertion (D/I) polymorphism to increase the risk for myocardial infarction (MI). The ACE D/I variant affects the renin-angiotensin system hormones that activate G-protein–coupled receptors. Genotyping at the ACE and GNB3 loci was performed on 585 patients with coronary artery disease with (n=270) or without (n=315) previous MI. Logistic regression analysis demonstrated a significant interaction between the ACE D allele and the GNB3 825T allele ( P <0.001). The odds ratio for MI, associated with the 825T allele, was not increased in the presence of the ACE II genotype (OR 0.5; P =0.09) but was significantly higher in 825T allele carriers with the ACE DI genotype (OR 1.9; P =0.01) and further increased in individuals with the ACE DD genotype (OR 2.4; P =0.02). The highest odds ratio was found in homozygous 825T allele carriers with the ACE DD genotype (OR 7.5; P =0.006). Our data suggest a significant interaction of the GNB3 825T allele with the ACE D allele in MI. These hypothesis-generating data may justify larger prospective studies.