Background.To study the impact of smoking and blood pressure conditional on serum total cholesterol levels, we investigated the 20-year mortality risk associated with high systolic blood pressure (≥140 mmHg) and smoking, at low (<5.2 mmol/Liter), medium (5.2–6.49mmol/Liter), and high (≥6.5 mmol/Liter) serum total cholesterol levels.Methods.The study population comprised a cohort of 50,000 men and women age 30–54 years, examined between 1974 and 1980, in five Dutch towns. The duration of follow-up averaged 20 years. Age-adjusted relative risks (RRs) for mortality from coronary heart disease (CHD), cardiovascular diseases (CVD) and all causes were estimated, for six risk profiles (based on levels of total cholesterol, systolic blood pressure and smoking), using Cox proportional hazards analysis.Results.Given a low cholesterol level, smoking had a larger impact than elevated blood pressure on CHD, CVD and all-cause mortality. The combination of elevated blood pressure and smoking among persons with low cholesterol was associated with RRs of 3.0 for CHD, 6.0 for CVD and 4.1 for all-cause mortality in men, and 2.3, 3.6 and 2.6, respectively, in women. Among persons with high cholesterol, the combination of high blood pressure and smoking was associated with RRs of 9.7 for CHD, 13.9 for CVD and 5.7 for all-cause mortality in men, and 15.9, 9.3 and 4.3, respectively, in women. For each risk profile, the absolute number of CHD, CVD and total deaths was larger in men than in women.Conclusions.The results demonstrate the potential power of a multifactorial approach to risk factor reduction in the prevention of cardiovascular diseases and all-cause mortality.