Established risk factors cannot explain all the variance in coronary heart disease (CHD). Immunoglobin E (IgE), a mediator of allergy, can affect platelets and arterial smooth muscle. We previously demonstrated a cross-sectional association between IgE and cardiovascular disease (CVD) in men. The present study evaluated this relationship prospectively in 278 men and 343 women followed for a mean of 8.9 years. There was an association between IgE and coronary disease in men, but not in women. There was no association for CVD, stroke, or all-cause mortality. The age-adjusted relative risk (RR) for coronary mortality in men with baseline IgE > or = 200 kU/L was 1.66 (p < or = 0.66), but for nonfatal myocardial infarction (MI) it was 6.46 (p < or = 0.01). This association was independent of smoking and other risk factors, and unrelated to allergy. Thus, elevated IgE was a strong independent prospective risk factor for nonfatal, but not fatal, MI in men.