BACKGROUND: The inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD) is well established. Questions remain about the association between HDL cholesterol and stroke, particularly for stroke subtypes. METHODS AND RESULTS: Cox survival models were applied to individual participant data from 25 cohort studies (about 80 000 subjects), with a median of 6.8 years follow-up. After adjustment for age and regression dilution, hazard ratios (95% confidence intervals) for a 1 standard deviation (SD) lower level of HDL cholesterol (0.4 mmol/L) were: for CHD events, 1.39 (1.22-1.57); for ischaemic stroke, 0.90 (0.75-1.07), and for haemorrhagic stroke, 0.89 (0.74-1.07). As total cholesterol (TC) increased relative to HDL cholesterol, the risk of CHD increased, the risk of ischaemic stroke was unchanged but the risk of haemorrhagic stroke decreased. A 1 SD increase in TC/HDL cholesterol (1.63 units) was associated with a 27% decrease in the risk of haemorrhagic stroke (95% confidence interval, 7-44%). CONCLUSION: There is clear evidence of potential benefit for CHD of increases in HDL cholesterol and decreases in TC relative to HDL cholesterol, but no evidence of an association between either HDL cholesterol or TC/HDL cholesterol and ischaemic stroke. Increasing HDL cholesterol relative to TC may increase the risk of haemorrhagic stroke.