Plasma levels of major essential antioxidants were determined in representative random samples of middleaged men from 16 European study populations which differed up to 6-fold in age-specific mortality from ischaemic heart disease (IHD). In 12 study populations having total plasma cholesterol in the medium range (5.7–6.2 mmol/1) and usual blood pressure, both these classical risk factors lacked a significant correlation to IHD mortality, whereas the absolute level of vitamin E (α-tocopherol) showed a strong inverse correlation (r2 = 0.63, P = 0.002). On evaluation of all study populations, cholesterol and diastolic blood pressure had a moderate direct association with IHD, but their importance still remained inferior to that of vitamin E as an inversely associated, presumably protective factor. In stepwise regression and multiple regression analysis, the IHD mortality of the study populations was predictable to 62% by lipid-standardized vitamin E, to 79% by vitamin E and total cholesterol, to 83% after inclusion of lipid-standardized vitamin A (retinol) and to 87% by all the above parameters plus diastolic blood pressure. In conclusion, in the present study the plasma status of vitamin E is the most important factor to explain cross-cultural differences of IHD mortality. This finding is consistent with the hypothesis of the prevention of arteriosclerosis by antioxidant protection against peroxidative lipoprotein modification, but does not exclude additional effects of antioxidant vitamins, e.g. on the cellular or immunological level.