The apolipoprotein (apo) E4 polymorphism is associated with increased risk for symptomatic coronary artery disease (CAD). This study examines whether the apo epsilon allele is associated with an increased risk for exercise-induced silent myocardial ischemia (SI) in healthy, older (62 +/- 7 years; mean +/- SD), normocholesterolemic, nonsmoking male volunteers. The apo epsilon 4 allele was present in 20 of 45 (44%) men with SI on graded exercise treadmill testing compared with 22 of 127 (17%) men of comparable age with normal exercise tests (P < .001), resulting in a crude relative risk of 2.57 (95% confidence limits, 1.57 to 4.23) for SI in men with the apo epsilon 4 allele compared with those without the epsilon 4 allele. Although the lipoprotein lipid levels did not differ between men with normal exercise tests and those with SI, the men with the apoE 4/3 phenotype had higher total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels than those with the apoE 2/3 and 3/3 phenotypes (P < .05). Men with SI and the apoE 4/3 phenotype were older (64 +/- 5 versus 57 +/- 8 years, P < .01) and leaner (P < .01) than the normal non-SI men with the apoE 4/3 phenotype. The older age of the men with SI and the apoE 4/3 phenotype is consistent with a progression of atherosclerosis over time. Men with SI and the apoE 3/3 phenotype were of comparable age and body composition to apoE 3/3 phenotype men with normal exercise tests. Thus, even in the presence of normal LDL-C levels, the apo epsilon 4 allele may predispose older men to SI.