The HOPE Study randomised 9500 high risk individuals aged >55 years, to Vitamin E (400 mg od) and/or Ramipril (10 mg od) or matching placebos, over 18 months from 267 centres in 19 countries. The trial was funded by the Canadian MRC, Hoechst Marion Roussel, Astra and Vitamin E manufacturers. The trial was stopped early by the DMSB, after a mean of 4–5 year follow-up because of significant benefit in the Ramipril arm. Non-trial baseline treatment: was 76% aspirin, 30% lipid lowering agents, 40% on beta blockade, 47% on calcium blockers, and 15% on diuretics. Baseline BP was 138/79 mmHg, which fell modestly (by 3.3/1.5 mmHg) on Ramipril. The primary outcome of death, MI or stroke was reduced by 22% (with tight confidence intervals) from 17.5% Ramipril to 13.9% Placebo (p = 0.0000002). The separate end points were also each significantly reduced (by 25%, 20% and 32% respectively). Revascularisation was reduced by 15% (p = 0.0013) and heart failure hospitalisation by 16% (p = 0.12). The results were particularly impressive in the 3518 diabetics, with CV death reduced 38%, MI 21%, stroke 32%, and all cause mortality 25%. The primary outcome was reduced from 19.6% Placebo to 15.3% Ramipril. The overall results were remarkably consistent across many pre-specified sub groups, divided by age, sex, and the presence/absence of diabetes, cardiovascular disease, coronary disease, or hypertension. The results were similar in those taking either beta blockers, calcium blockers, or diuretics compared with those not taking the respective drug. The benefit was greater in those with higher usual systolic BP at baseline, but benefit was apparent down to baseline SBP of 125–130 mmHg. Only about half the stroke benefit and one quarter of the MI benefit could be attributed to BP reduction by Ramipril. Ramipril rapidly reduces the risk of serious events in patients with evidence of prior vascular disease, or in diabetics with some additional risk factor; this result was seen on top of high use of current treatments for hypertension or ischaemia. There was a 5% drop out from side effects (mainly cough). There was neither benefit, nor harm from Vitamin E. New data from sub studies in diabetic patients, and of changes in the carotid wall, support an effect which is independent of blood pressure.