An association between ABO blood group and myocardial infarction (MI) has been described. One probable mechanism underlying this association is the influence of ABO blood group on plasma von Willebrand factor (vWF) levels. We conducted this genetic study to test whether the ABO O1 allele is associated with low vWF plasma levels and with a reduced risk of MI. Cases consisted of 793 consecutive, angiographically examined patients with either acute or prior MI. As controls served 340 angiographically examined patients with neither coronary artery disease nor signs of MI. ABO1 locus alleles (A1, A2, B, O1, O2) were identified with polymerase chain reaction and fluorogenic probes. The distribution of O1 alleles in the MI group versus the control group was: no O1 allele (15.4%/10.0%), one O1 allele (49.7%/50.0%) and two O1 alleles (34.9%/40.0%) (P = 0.035). O1 allele carriage was associated with a 39% reduction in the risk of MI unadjusted odds ratio, 0.61; 95% confidence interval, 0.41-0.91). The significant association was maintained after adjustment for other cardiovascular risk factors. vWF antigen levels correlated with the number of O1 alleles (P = 0.00003) in a separate control group (n = 164). Carriage of the O1 allele is associated with a decreased risk of myocardial infarction, with homozygosity providing the greatest protection.