Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly because of their relatively short duration. The objective of this study was to evaluate whether or not long-term supplementation with vitamin E decreases the risk of cancer, cancer death and major cardiovascular events. A randomised, double-blind, placebo-controlled international trial [the initial Heart Outcomes Prevention Evaluation (HOPE) trial, conducted between December 21, 1993, and April 15, 1999] of patients at least 55 years old with vascular disease or diabetes mellitus was extended [HOPE – The Ongoing Outcomes (HOPE-TOO)] between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centres that had enrolled 9541 patients, 174 centres participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centres, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention and 738 agreed to passive follow-up. The median duration of the follow-up was 7.0 years. Daily doses were of natural source vitamin E (400 IU) or matching placebo. Primary outcomes included cancer incidence, cancer deaths and major cardiovascular events (myocardial infarction, stroke and cardiovascular death). Secondary outcomes included heart failure, unstable angina and revascularisations. Among all HOPE patients there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs. 586 (12.3%) in the placebo group; for cancer deaths there were 156 (3.3%) vs. 178 (3.7%), respectively; and for major cardiovascular events there were 1022 (21.5%) vs. 985 (20.6%), respectively. Patients in the vitamin E group had a higher risk of heart failure and hospitalisation for heart failure. Similarly, among patients enrolled at the centres participating in the HOPE-TOO trial there were no differences in cancer incidence, cancer deaths and major cardiovascular events, but higher rates of heart failure and hospitalisations for heart failure.