BACKGROUND: Age, sex, and blood pressure could modify the associations of total cholesterol (and its main two fractions, HDL and LDL cholesterol) with vascular mortality. This meta-analysis combined prospective studies of vascular mortality that recorded both blood pressure and total cholesterol at baseline, to determine the joint relevance of these two risk factors. METHODS: Information was obtained from 61 prospective observational studies, mostly in western Europe or North America, consisting of almost 900,000 adults without previous disease and with baseline measurements of total cholesterol and blood pressure. During nearly 12 million person years at risk between the ages of 40 and 89 years, there were more than 55,000 vascular deaths (34,000 ischaemic heart disease [IHD], 12,000 stroke, 10,000 other). Information about HDL cholesterol was available for 150,000 participants, among whom there were 5000 vascular deaths (3000 IHD, 1000 stroke, 1000 other). Reported associations are with usual cholesterol levels (ie, corrected for the regression dilution bias). FINDINGS: 1 mmol/L lower total cholesterol was associated with about a half (hazard ratio 0.44 [95% CI 0.42-0.48]), a third (0.66 [0.65-0.68]), and a sixth (0.83 [0.81-0.85]) lower IHD mortality in both sexes at ages 40-49, 50-69, and 70-89 years, respectively, throughout the main range of cholesterol in most developed countries, with no apparent threshold. The proportional risk reduction decreased with increasing blood pressure, since the absolute effects of cholesterol and blood pressure were approximately additive. Of various simple indices involving HDL cholesterol, the ratio total/HDL cholesterol was the strongest predictor of IHD mortality (40% more informative than non-HDL cholesterol and more than twice as informative as total cholesterol). Total cholesterol was weakly positively related to ischaemic and total stroke mortality in early middle age (40-59 years), but this finding could be largely or wholly accounted for by the association of cholesterol with blood pressure. Moreover, a positive relation was seen only in middle age and only in those with below-average blood pressure; at older ages (70-89 years) and, particularly, for those with systolic blood pressure over about 145 mm Hg, total cholesterol was negatively related to haemorrhagic and total stroke mortality. The results for other vascular mortality were intermediate between those for IHD and stroke. INTERPRETATION: Total cholesterol was positively associated with IHD mortality in both middle and old age and at all blood pressure levels. The absence of an independent positive association of cholesterol with stroke mortality, especially at older ages or higher blood pressures, is unexplained, and invites further research. Nevertheless, there is conclusive evidence from randomised trials that statins substantially reduce not only coronary event rates but also total stroke rates in patients with a wide range of ages and blood pressures.