Context Vigorous physical exertion transiently increases the risk of acute myocardial infarction (MI), but little is known about the clinical characteristics of exertion-related MI. Objective To compare the clinical and angiographic characteristics of patients who had an exertion-related acute MI vs those who experienced an MI not related to exertion. Design and Setting Prospective observational cohort study of patients with an acute MI referred to a tertiary care hospital for primary angioplasty. Patients Of 1048 patients with acute MI, 640 (64 who experienced an exertion-related MI and 576 who did not) were selected for treatment with primary angioplasty and admitted between August 1995 and November 1998. Main Outcome Measures Clinical characteristics of the patients, including their habitual physical activity (determined by the Framingham Physical Activity Index and the Lipid Research Clinic Physical Activity Questionnaire), angiographic findings during coronary angiography, and the relative risk (RR) of MI during exertion. Results Patients who experienced exertion-related MI were more frequently men (86% vs 68%), hyperlipidemic (62% vs 40%), and smokers 59% vs 37%), were more likely to present with ventricular fibrillation (20% vs 11%), Killip classification III or IV heart failure (44% vs 22%), single-vessel disease (50% vs 28%), and a large thrombus in the infarct artery (64% vs 35%) and were more likely to be classified as having very low or low activity (84% vs 66%). The RR of experiencing an MI during exertion was 10.1 times greater than the risk at other times (95% confidence interval [CI], 1.6-65.6), with the highest risk among patients classified as very low active (RR, 30.5; 95% CI, 4.4-209.9) and low active (RR, 20.9; 95% CI, 3.1-142.1). Conclusion These results show that exertion-related Mts occur in habitually inactive people with multiple cardiac risk factors. These individuals may benefit from mod est exercise training and aggressive risk-factor modification before they perform vigorous physical activity.