Few data exist regarding the association of risk factor burden in middle age with lifetime risks for cardiovascular disease (CVD) and non-CVD death. In this study, participants in the Chicago Heart Association Detection Project in Industry aged 40 to 59 years in 1967 to 1973 were stratified into 5 groups on the basis of risk factor burden: favorable risk factor profile (untreated blood pressure <or=120/<or=80 mm Hg, total cholesterol <200 mg/dl, nonsmoking, and body mass index <25 kg/m2); 0 elevated but >or=1 unfavorable; or any 1, any 2, or >or=3 elevated (systolic >or=140 mm Hg or diastolic >or=90 mm Hg or treated hypertension; total cholesterol >or=240 mg/dl; current smoking; or body mass index >or=30 kg/m2). Remaining lifetime risks for CVD and non-CVD death were estimated through the age of 85 years. Eight thousand thirty-three men and 6,493 women were followed for 409,987 person-years; 2,582 died of CVD, and 3,955 died of non-CVD causes. A greater risk factor burden was associated with a higher incidence of CVD and non-CVD death. Compared with participants with >or=3 risk factors, those with favorable profiles had substantially lower lifetime risks for CVD death (20.5% vs 35.2% in men, 6.7% vs 31.9% in women) and markedly longer median Kaplan-Meier survival (>35 vs 26 years in men, >35 vs 28 years in women). In conclusion, having favorable risk factors in middle age is associated with a lower lifetime risk for CVD death and markedly longer survival. These results should encourage efforts aimed at preventing the development of risk factors in younger subjects to decrease CVD mortality and promote longevity.