Myocardial infarction (MI) occurs as the result of complex interactions of multiple genetic and environmental factors. By conducting a genome wide association study in a Japanese population using 210,785 single nucleotide polymorphism (SNP) markers, we identified a novel susceptible locus for MI on chromosome 5p15.3. An SNP (rs11748327) in this locus showed significant association in several independent cohorts (combined P = 5.3 × 10(-13), odds ratio = 0.80, comparison of allele frequency). Association study using tag SNPs in the same linkage disequilibrium block revealed that two additional SNPs (rs490556 and rs521660) conferred risk of MI. These findings indicate that the SNPs on chromosome 5p15.3 are novel protective genetic factors against MI.