A synergistic interaction between the insertion/deletion (I/D) polymorphism within the angiotensin-converting enzyme (ACE) gene and an A/C transversion at nucleotide position 1166 within the angiotensin II sub-type 1 receptor (AT1R) gene on risk of myocardial infarction has been reported. The risk associated with the ACE DD genotype increased with the number of AT1R C alleles present. To investigate this further, ACE I/D and AT1R A1166C genotypes were determined in 541 cases recruited at the time of infarction and 507 population-based controls. There was no difference in either the genotype distribution or allele frequencies between cases and controls for either the ACE polymorphism (P=0.48 and 0.35 respectively) or the AT1R polymorphism (P=0.35 and 0.21 respectively). Odds ratios for risk of MI associated with the ACE DD and AT1R CC genotypes were 1.09 (95% CI, 0.82-1.45) and 1.06 (0.67-1.68) respectively. 3.1% of cases versus 3.6% of controls were homozygous for both the D and C alleles (P=0.71). There was no increase in risk associated with the DD genotype in the presence of either one or two AT1R C alleles in the whole cohorts (OR 0.99, 95% CI 0.65-1.51 and 0.76, 95% CI 0.30-1.88, respectively) nor in sub-groups defined by specific risk factors. In conclusion, no evidence was found to support any interaction between the ACE gene I/D polymorphism and the ATIR gene A1166C transversion in determining the risk of myocardial infarction in the population studied.