It has been suggested that people with the epsilon4 allele of the apolipoprotein E (apoE) polymorphism and the deletion (D) allele of the insertion (I/D) polymorphism of angiotensin-converting enzymes, are at a greater risk for coronary artery disease. However, only a few studies have examined the relationships between vasospastic angina (VSA) and genotype, especially with the apoE polymorphism. In the present study, 76 patients with VSA without significant fixed coronary artery stenosis, 149 patients with ischemic heart disease (IHD) who had 75% or more luminal diameter narrowing and 213 healthy subjects were enrolled. The odds ratio for VSA of the epsilon4 allele carriers relative to the epsilon3/3 allele subjects compared with subjects with IHD and control subjects combined was 0.44 (95% CI 0.21 to 0.93, P=0.021), and that compared with control subjects alone was 0.36 (95% CI 0.17 to 0.78, P=0.005), implying that the presence of the epsilon4 allele indicates resistance to the development of VSA. In contrast, people with the epsilon2 allele showed a tendency to develop VSA more frequently than did patients with IHD (P=0.009), although the frequency of the epsilon2 allele did not differ between patients with VSA and control subjects. On the other hand, no recessive and dominant effects of the D alleles on VSA were found. These findings suggest that the risk of the occurrence of VSA may be reduced by the epsilon4 allele and increased by the epsilon2 allele. The ApoE polymorphism may be associated with IHD and VSA, probably due to the modulation of lipid metabolism.