To evaluate the role of habitual exertion in the development and manifestation of coronary artery disease, 36 well-conditioned men with acute coronary syndromes (4 with unstable angina, 23 with acute myocardial infarction and 9 survivors of sudden ischemic death) related to sports were compared with 36 sedentary men with the same syndromes occurring at rest. The mean age of the study subjects was 48 years (range 25 to 65). Patients exercised on average 6 hours/week (range 2 to 15) for greater than or equal to 10 years (range 10 to 45). Coronary angiography was performed within 4 hours after the onset of symptoms. The well-conditioned men had fewer risk factors than the inactive men (control subjects): fewer of them smoked (58 vs 94%, odds ratio 0.08) or had serum total cholesterol levels greater than or equal to 240 mg/dl (14 vs 56%, odds ratio 0.13, both p <0.05). In addition, these men had less diseased (28 vs 72%, odds ratio 0.15, p <0.02) and less severely stenotic (36 vs 78%, odds ratio 0.16, p <0.03) coronary arteries. The association between activity levels and angiographic disease severity remained significant after correction for risk factors. Lesion morphology, site of the lesion and presence of thrombus of the culprit artery and diameter and dominance of all coronary arteries did not differ between the well-conditioned men and control subjects. This study suggests that regular strenuous exercise can reduce coronary artery disease and shows a common pathogenesis for acute coronary syndromes related and unrelated to sport.