Background Vitamin E (α-tocopherol) is thought to have a role in prevention of atherosclerosis, through inhibition of oxidation of low-density lipoprotein. Some epidemiological studies have shown an association between high dietary intake or high serum concentrations of α-tocopherol and lower rates of ischaemic heart disease. We tested the hypothesis that treatment with a high dose of α-tocopherol would reduce subsequent risk of myocardial infarction (MI) and cardiovascular death in patients with established ischaemic heart disease. Methods In this double-blind, placebo-controlled study with stratified randomisation, 2002 patients with angiographically proven coronary atherosclerosis were enrolled and followed up for a median of 510 days (range 3-981). 1035 patients were assigned α-tocopherol (capsules containing 800 IU daily for first 546 patients; 400 IU daily for remainder); 967 received identical placebo capsules. The primary endpoints were a combination of cardiovascular death and non-fatal MI as well as non-fatal Ml alone. Findings Plasma α-tocopherol concentrations (measured in subsets of patients) rose in the actively treated group (from baseline mean 34·2 μmol/L to 51·1 μmol/L with 400 IU daily and 64·5 μmol/L with 800 IU daily) but did not change in the placebo group. α-tocopherol treatment significantly reduced the risk of the primary trial endpoint of cardiovascular death and non-fatal Ml (41 vs 64 events; relative risk 0·53 [95% Cl 0·34-0·83; p=0·005). The beneficial effects on this composite endpoint were due to a significant reduction in the risk of non-fatal Ml (14 vs 41; 0·23 [0·11-0·47]; p=0·005); however, there was a non-significant excess of cardiovascular deaths in the α-tocopherol group (27 vs 23; 1·18 [0·62-2·27]; p=0·61). All-cause mortality was 36 of 1035 α-tocopherol-treated patients and 27 of 967 placebo recipients. Interpretation We conclude that in patients with angiographically proven symptomatic coronary atherosclerosis, α-tocopherol treatment substantially reduces the rate of non-fatal MI, with beneficial effects apparent after 1 year of treatment. The effect of α-tocopherol treatment on cardiovascular deaths requires further study.