We investigated whether the Framingham risk score, which was designed to estimate the 10-year risk of coronary heart disease (CHD), differentiates lifetime risk for CHD. All subjects in the Framingham Heart Study examined from 1971 to 1996 who were free of CHD were included. Subjects were stratified into age- and gender-specific tertiles of Framingham risk score, and lifetime risk for CHD was estimated. We followed 2,716 men and 3,500 women; 939 developed CHD and 1,363 died free of CHD. At age 40 years, in risk score tertiles 1, 2, and 3, respectively, the lifetime risks for CHD were 38.4%, 41.7%, and 50.7% for men and 12.2%, 25.4%, and 33.2% for women. At age 80 years, risks were 16.4%, 17.4%, and 38.8% for men and 12.8%, 22.4%, and 27.4% for women. The Framingham risk score stratified lifetime risk well for women at all ages. It performed less well in younger men but improved at older ages as remaining life expectancy approached 10 years. Lifetime risks contrasted sharply with shorter term risks: at age 40 years, the 10-year risks of CHD in tertiles 1, 2, and 3, respectively, were 0%, 2.2%, and 11.6% for men and 0%, 0.7%, and 2.3% for women. The Framingham 10-year CHD risk prediction model discriminated short-term risk well for men and women. However, it may not identify subjects with low short-term but high lifetime risk for CHD, likely due to changes in risk factor status over time. Further work is needed to generate multivariate risk models that can reliably predict lifetime risk for CHD.