Evidence explainerVitamin E (natural d-alpha vs synthetic dl-alpha tocopherol)

Vitamin E for Your Heart? Three Big Trials Found No Benefit, and Some Found Harm

Vitamin E looked promising in observational studies. Then more than 60,000 people took it in long randomized trials. Here is what happened.

By Kymata Health editorial teamPublished October 9, 2026Last reviewed October 9, 2026

Medical review pending. Written by our editorial team from the studies cited below; a credentialed clinician has not reviewed it yet. Educational only, not medical advice.

Key takeaways

  • HOPE (9,541 high-risk adults, 400 IU/day natural vitamin E) found no change in major cardiovascular events (RR 1.04) and more heart failure (RR 1.13) [2].
  • The Women's Health Study (39,876 healthy women, 600 IU every other day for about 10 years) found no significant drop in major cardiovascular events (RR 0.93) [3].
  • The Physicians' Health Study II (14,641 men, 400 IU every other day for 8 years) found no effect on major events (HR 1.01) and more hemorrhagic stroke (HR 1.74) [4].
  • In SELECT, 400 IU/day of synthetic vitamin E raised prostate cancer by 17% in healthy men [5].
  • A meta-analysis of 19 trials linked 400 IU/day or more to slightly higher mortality [6].

The evidence, graded

Pulled from our monograph evidence tables. Grades follow our evidence-grading policy.

  • No effectNo effectMajor heart and blood-vessel events in high-risk adults (HOPE / HOPE-TOO)Vitamin E (natural d-alpha vs synthetic dl-alpha tocopherol) · RCT · n=9,541 · 2005 · PMID 15769967No difference in major cardiovascular events (RR 1.04; 95% CI 0.96-1.14), cancer incidence or cancer deaths. Heart failure (RR 1.13) and hospitalization for heart failure (RR 1.21) were higher with vitamin E.
  • No effectNo effectMajor heart and blood-vessel events in healthy women (WHS)Vitamin E (natural d-alpha vs synthetic dl-alpha tocopherol) · RCT · n=39,876 · 2005 · PMID 15998891Major cardiovascular events were not significantly reduced (RR 0.93; 95% CI 0.82-1.05), nor were total cancer or total mortality. Cardiovascular death was 24% lower (RR 0.76), a secondary finding.
  • No effectNo effectMajor heart and blood-vessel events in men 50+ (PHS II)Vitamin E (natural d-alpha vs synthetic dl-alpha tocopherol) · RCT · n=14,641 · 2008 · PMID 18997197No effect on major cardiovascular events (HR 1.01; 95% CI 0.90-1.13) or total mortality, but a higher risk of hemorrhagic stroke (HR 1.74; 95% CI 1.04-2.91).
  • Grade BImprovedProstate outcome in healthy men (SELECT extended follow-up)Vitamin E (natural d-alpha vs synthetic dl-alpha tocopherol) · RCT · n=34,887 · 2011 · PMID 21990298Prostate cancer was 17% more common with vitamin E than placebo (HR 1.17; 99% CI 1.004-1.36): 620 vs 529 men, an absolute increase of 1.6 per 1000 person-years.
  • Grade CImprovedAll-cause mortality with high-dosage vitamin EVitamin E (natural d-alpha vs synthetic dl-alpha tocopherol) · Meta-analysis · n=135,967 · 2005 · PMID 15537682Trials of ≥400 IU/d showed 39 more deaths per 10,000 persons (95% CI 3 to 74); low-dosage trials showed no increase. Risk rose with dosages above 150 IU/d.

Why people hoped it would work

Vitamin E is a fat-soluble antioxidant, and observational studies suggested that people with high vitamin E intakes from food or supplements had fewer heart problems [3][1]. Those studies cannot separate the vitamin from the kind of person who takes it, so the long randomized trials below were the real test.

HOPE: high-risk adults, 400 IU a day

HOPE enrolled 9,541 adults aged at least 55 with vascular disease or diabetes, and gave 400 IU/day of natural-source vitamin E or placebo; the HOPE-TOO extension brought median follow-up to 7.0 years [2].

Major cardiovascular events were no lower (21.5% vs 20.6%; RR 1.04), and cancer rates did not differ [2]. Heart failure was more common with vitamin E (RR 1.13), as were hospital stays for heart failure (RR 1.21) [2]. ODS calls the HOPE trials compelling evidence that these doses do not reduce serious cardiovascular events in men and women over 50 with heart disease or diabetes [1].

Women's Health Study: healthy women, 10 years

In 39,876 healthy US women aged 45 and older, 600 IU of natural-source vitamin E on alternate days for an average of 10.1 years gave a non-significant 7% drop in major cardiovascular events (RR 0.93) [3]. Heart attack and stroke were unchanged, and total cancer did not differ [3].

One secondary result stood out: cardiovascular deaths were 24% lower (RR 0.76) [3]. With the main outcome flat, the authors concluded the data do not support vitamin E for these purposes in healthy women [3].

Physicians' Health Study II: men over 50

The trial gave 14,641 US male physicians aged 50 and older 400 IU of vitamin E every other day, vitamin C, both or placebo, for a mean of 8 years [4]. Vitamin E had no effect on major cardiovascular events (HR 1.01), heart attacks or stroke overall [4].

It was linked to more hemorrhagic stroke (HR 1.74) [4]. ODS notes that most of these physicians also took aspirin, so the finding may reflect a combined bleeding tendency [1].

The harm signals in one place

None of these is proof on its own, but together they explain why ODS frames high-dose vitamin E as a safety question. The signals so far:

  • Heart failure: RR 1.13 in HOPE, a secondary outcome [2].
  • Hemorrhagic stroke: HR 1.74 in the Physicians' Health Study II [4].
  • Prostate cancer: 620 vs 529 cases with 400 IU/day of synthetic vitamin E in SELECT (HR 1.17), in 34,887 men [5].
  • Mortality: 39 more deaths per 10,000 people in trials of 400 IU/day or more, across 19 trials; the authors note those trials were often small and in people with chronic diseases [6].

Quick answers

Did natural vitamin E do better than synthetic in these trials?

HOPE and the Women's Health Study used natural-source vitamin E and found no reduction in major cardiovascular events [2][3]. SELECT used synthetic vitamin E [5]. For the label math, see 400 IU in mg, natural vs synthetic.

How does my multivitamin compare with the trial doses?

The trials tested 400 to 600 IU [2][3][4], which is about 180 to 402 mg depending on the form [1]. The adult RDA is 15 mg, so compare the mg on your label with both numbers [1].

Should I stop vitamin E before surgery?

High-dose vitamin E may raise bleeding risk, especially with blood thinners [1]. Tell your surgeon and clinician about every supplement you take.

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References

  1. [1]Vitamin E: Fact Sheet for Health Professionals. NIH Office of Dietary Supplements, 2021.
  2. [2]Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA, 2005. PMID 15769967
  3. [3]Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA, 2005. PMID 15998891
  4. [4]Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial. JAMA, 2008. PMID 18997197
  5. [5]Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA, 2011. PMID 21990298
  6. [6]Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med, 2005. PMID 15537682

Vitamin E (natural d-alpha vs synthetic dl-alpha tocopherol) and other dietary supplements are not intended to diagnose, treat, cure or prevent any disease, and these statements have not been evaluated by the FDA. Talk to your clinician or pharmacist before starting a supplement, especially if you take prescription medicines. This page has no product or affiliate links.

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