Introduction Coronary heart disease (CHD) remains a leading cause of death in the United States. The Framingham Risk Score (FRS) was developed to help clinicians in determining their patients' CHD risk. We hypothesize that the FRS will be significantly predictive of CHD events among men in the Aerobics Center Longitudinal Study (ACLS) population. Methods Our study consisted of 34,557 men who attended the Cooper Clinic in Dallas, Texas, for a baseline clinical examination from 1972 through 2002. CHD events included self-reported myocardial infarction or revascularization or death due to CHD. During the 12-year follow-up 587 CHD events occurred. Multivariable-adjusted hazard ratios generated from ACLS analysis were compared with the application of FRS to the Framingham Heart Study (FHS). Results The ACLS cohort produced similar hazard ratios to the FHS. The adjusted Cox proportional hazard model revealed that men with total cholesterol of 280 mg/dL or greater were 2.21 (95% confidence interval (CI), 1.59-3.09) times more likely to have a CHD event than men with total cholesterol from 160 through 199mg/dL; men with diabetes were 1.63 (95% CI, 1.35-1.98) times more likely to experience a CHD event than men without diabetes. Conclusion The FRS significantly predicts CHD events in the ACLS cohort. To the best of our knowledge, this is the first report of a large, single-center cohort study to validate the FRS by using extensive laboratory and clinical measurements.