An attenuated heart rate (HR) response to exercise, or chronotropic incompetence, has been shown to predict adverse cardiac events in subjects without known cardiovascular disease (CVD). The aim of the present study was to investigate whether chronotropic incompetence independently predicts acute myocardial infarction (AMI) in middle-aged men. In addition to previously established chronotropic incompetence variables, we focused on a new chronotropic incompetence variable, the HR increase from 40% to 100% of maximal work capacity (HR40-100), as a predictor of AMI. The subjects were a representative sample of 1,176 middle-aged men who did not have CVD and did not use HR-lowering medication at baseline. The association of chronotropic incompetence variables with the risk of AMI was examined by Cox regression models including numerous known risk factors for AMI. During an average follow-up of 11.0 years, there were 106 AMIs (9.0%). In Cox multivariable model, the risk of AMI increased by 33% for each SD decrement of 13 beats/min in HR40-100 (95% confidence interval [CI] 9 to 64). When considered concurrently, HR40-100 was the only chronotropic incompetence variable that improved the predictive value of the model containing other risk factors for AMI. Men with a low HR40-100 (<46 beats/min) and a heightened increase in systolic blood pressure (SBP) (>67 mm Hg) were at particularly high risk, with a 3.1-times higher incidence of AMI than those with a normal HR40-100 and SBP increase (95% CI 1.7 to 5.7). In conclusion, a low HR40-100 predicted AMI in men without previous CVD independent of other exercise test or clinical variables.