Endothelin-1 has been implicated in atherosclerotic and ischemic heart disease. No population-based studies have examined the association of endothelin-1 with coronary heart disease (CHD). We performed a cross-sectional analysis of 961 older women and men. CHD was defined as a history of myocardial infarction, coronary surgery, angina, or major Q-wave abnormality on electrocardiography. We examined the association of endothelin-1 with CHD after adjusting for known risk factors and atherosclerosis measures. A total of 248 women and 156 men had CHD. Median endothelin-1 levels were similar by gender and higher among those with versus those without CHD (3.3 vs 3.1 pg/ml, p <0.001). After adjusting for age, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, hypertension, diabetes, alcohol use, exercise, aspirin, cholesterol-lowering medication, and hormone therapy use, endothelin-1 had a stronger association with CHD in women (odds ratio [OR] 3.02, (95% confidence interval 1.43 to 6.37) than in men (OR 1.82, 95% confidence interval 0.74 to 4.51). Age modified the effect of endothelin-1 with CHD in men (OR 0.47 for age <75 years vs 3.84 in men >or=75 years, p = 0.05 for interaction). Further adjustment for ankle-brachial index and carotid intima media thickness did not alter these results. In conclusion, higher endothelin-1 levels are independently associated with CHD in women of all ages and among older men only.