A 23-year follow-up study of 10,059 40- to 65-year-old participants in the Israeli Ischemic Heart Disease Study found that of 3473 deaths (34.5%), in 1098 (10.9%) coronary heart disease (CHD) was the underlying cause. Total serum cholesterol (TC) was measured in 9902 individuals. During the study, CHD mortality was elevated primarily in individuals in quintiles 4 and 5 (TC levels greater than or equal to 217 mg/dl). Although CHD mortality increased marginally with increasing TC at levels below 217 mg/dl, this was entirely explained by age and other correlated risk factors in a multivariate adjustment of the survival curves. The "net" 23-year survival in terms of CHD was 87% in quintile 5 (TC greater than 241) versus 93% in quintile 1 (TC less than 176 mg/dl). CHD mortality was inversely related to the percent of cholesterol in high density lipoprotein (PHDL). All-cause mortality increased only when TC was above 240 mg/dl and in the subjects with PHDL levels in the lowest 20%. Lipids appeared to be somewhat less effective in predicting subsequent CHD mortality than did hypertension and smoking and were clearly secondary in assessing risk of all-cause death. The results raise the question whether intensive treatment for hypercholesterolemia is indicated for men at "borderline" levels. We conclude that the association between serum cholesterol and long-term mortality partly reflects the role that levels of co-existing CHD risk factors play in prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)