The Multiple Risk Factor Intervention Trial evaluated a multifactor intervention on coronary heart disease (CHD) in 12 866 men. A priori defined endpoints (CHD death, CHD death or nonfatal myocardial infarction, cardiovascular disease [CVD] death, and all-cause death) did not differ significantly between the special intervention (SI) and usual care (UC) groups over an average follow-up period of 7 years. Event rates were lower than anticipated, reducing power. Other nonfatal CVD outcomes were prespecified but not considered in composite outcomes comparing SI with UC. Post-trial CVD mortality risks associated with nonfatal CVD events occurring during the trial were determined with Cox regression. Nonfatal outcomes associated with >2-fold risk of CVD death over the subsequent 20 years were combined with during-trial deaths to create 2 new composite outcomes. SI/UC hazard ratios and 95% confidence intervals were estimated for each composite outcome. Of 10 during-trial nonfatal events, 6 were associated (P<0.001) with >2-fold risk of CVD death. A CHD composite outcome (CHD death, myocardial infarction [clinical or serial ECG change], CHF, or coronary artery surgery) was experienced by 520 SI and 602 UC men (SI/UC hazard ratio = 0.86; 95% confidence interval, 0.76-0.97; P=0.01). A CVD composite outcome (CHD [as above], other CVD deaths, stroke, or renal impairment) was experienced by 581 SI and 652 UC men (hazard ratio = 0.89; 95% confidence interval, 0.79-0.99; P=0.04). In post hoc analyses, composite fatal/nonfatal CHD and CVD rates over 7 years were significantly lower for SI than for UC. These findings reinforce recommendations for improved dietary/lifestyle practices, with pharmacological therapy as needed, to prevent and control major CVD risk factors.