Heme oxygenase-1 (HO-1) has been suggested to have antiatherogenic properties. This study was designed to examine the relationship between the HO-1 gene (HMOX1) and ischemic heart disease. The study population consisted of 1972 control subjects and 597 subjects with ischemic heart disease (myocardial infarction (MI) n = 393, HMOX1 n = 204). The control subjects were consecutively selected from the Suita study, an epidemiological cohort representing the general population in Japan. Patients with ischemic heart disease were recruited from the outpatient clinic of the National Cardiovascular Center (NCVC). We sequenced HMOX1 and found a T(-413)A polymorphism in the promoter region. Multiple logistic analyses indicated that the T(-413)A (T(-413)A (TA + TT/AA) polymorphism, sex, smoking habit, DM and BMI affected the occurrence of ischemic heart disease. The odds ratios of the TA + TT allele for MI and AP were 1.42 (P = 0.0468, 95% confidence interval: 0.01-0.35) and 1.86 (P = 0.0096, 95% confidence interval: 0.08-0.55), respectively. Luciferase reporter assay indicated that the A allele promoter had significantly higher activity than the T allele promoter. The AA genotype of HMOX1 reduced the incidence of ischemic heart disease, possibly due to the high expression level of HMOX1.