Essential antioxidants were determined in plasma of middle-aged men representing 16 European study populations, which differed sixfold in age-specific mortality from ischemic heart disease (IHD). In 12 populations with "common" plasma cholesterol (5.7-6.2 mmol/L) and blood pressure, both classical risk factors lacked significant correlations to IHD mortality, whereas absolute levels of vitamin E (alpha-tocopherol) showed a strong inverse correlation (r2 = 0.63, P = 0.002). Evaluating all populations, cholesterol and diastolic blood pressure were moderately associated, but their correlation was inferior to that of vitamin E. In stepwise regression and multiple regression analysis, mortality was predictable to 62% by lipid-standardized vitamin E, to 79% by vitamin E and cholesterol, to 83% after inclusion of lipid-standardized vitamin A (retinol), and to 87% by all the above parameters plus blood pressure. Thus, in the present study the cross-cultural differences of IDH mortality are primarily attributable to plasma status of vitamin E, which might have protective functions.