Coronary artery disease is associated with multiple genetic and environmental risk factors. In this study, we evaluated the correlation of angiotensin l-converting enzyme (ACE) (I/D) and ApoE gene polymorphisms (E2, E3, E4 and g.-219G/T) with myocardial perfusion. We examined 410 patients using exercise-rest myocardial perfusion single photon emission computed tomography (SPECT), in which the summed stress score (SSS), summed rest score (SRS) and summed difference score (SDS) indexes were calculated. Homozygotes for the ACE D allele had greater mean values of SSS (P<0.001) and SDS (P<0.001). In addition, E3 homozygotes, E4 heterozygotes and E4 homozygotes had significantly higher values of SSS and SDS compared with E3 heterozygotes (P<0.001); E4 homozygotes had significantly higher values of SSS and SDS compared with E3 homozygotes. Furthermore, for the g.-219G>T polymorphic site at the promoter region of ApoE gene, the mean values of SSS and SDS were significantly higher for T heterozygotes/homozygotes than for GG homozygotes. Adjusting for all demographic and clinical data using multiple linear regression analysis it was found that ACE D and both ApoE genotypes were independent predictors with a cumulative contribution for the prediction of SSS and SDS. Furthermore, logistic regression analysis revealed that all three genotypes had an independent predictive ability for abnormal SSS (SSS>2). These data provide the first evidence of an association and significant cumulative contribution of the aforementioned genotypes in myocardial perfusion with E4 allele having the strongest association followed by ACE D and ApoE g.-219T alleles.