Background —The −344C allele of a 2-allele (C or T) polymorphism in the promoter of the gene encoding aldosterone synthase (CYP11B2) is associated with increased left ventricular size and mass and with decreased baroreflex sensitivity, known risk factors for morbidity and mortality associated with myocardial infarction (MI). We hypothesized that this polymorphism was a risk factor for MI. Methods and Results —We used a nested case-control design to investigate the relationships between this polymorphism and the risk of nonfatal MI in 141 cases and 270 matched controls from the Helsinki Heart Study, a coronary primary prevention trial in dyslipidemic, middle-aged men. There was a nonsignificant trend of increasing risk of MI with number of copies of the −344C allele. However, this allele was associated in a gene dosage–dependent manner with markedly increased MI risk conferred by classic risk factors. Whereas smoking conferred a relative risk of MI of 2.50 ( P =0.0001) compared with nonsmokers in the entire study population, the relative risk increased to 4.67 in −344CC homozygous smokers (relative to nonsmokers with the same genotype, P =0.003) and decreased to 1.09 in −344TT homozygotes relative to nonsmokers with this genotype. Similar joint effects were noted with genotype and decreased HDL cholesterol level as combined risk factors. Conclusions —Smoking and dyslipidemia are more potent risk factors for nonfatal MI in males who have the −344C allele of CYP11B2.