Elevated mortality has been reported at extremes of the serum total cholesterol distribution, with increased coronary mortality reported at high total cholesterol levels and increased cancer and non-cardiovascular/non-cancer mortality at low total cholesterol levels. The authors used data collected on 1,959 males aged 35-69 years from the fourth Framingham Study examination to analyze the relations between total serum cholesterol levels and 409 coronary deaths, 325 cancer deaths, and 534 other deaths for a 32-year follow-up. Age- and risk factor-adjusted Cox regressions were computed. Nonlinear (U-shaped) relations were investigated with the use of quadratic regression and with dummy variables using the 160-199 mg/dl group as the comparison group. Subset analyses investigated the relation in smokers and men who drank > or = 14 alcoholic drinks per week. All analyses were repeated removing those with existing cardiovascular disease and cancer and those who died during the first 5 years of follow-up. A significant U-shaped relation with all-cause mortality was noted, as were an inverse relation to cancer mortality and a monotonic increasing relation with coronary disease mortality. In subset analyses, the association of low serum cholesterol (< 160 mg/dl) with cancer mortality was observed in men who smoked cigarettes. Compared with the 160-199 mg/dl group, the relative risk was 3.72 (p = 0.0001, 95% confidence interval 1.91-7.25). Studies of the relation of low total serum cholesterol levels, cigarette smoking, and cancer are needed.