A meta-analysis was performed of the dose–response relationship between vitamin E supplementation and total mortality using data from RCTs. 135 967 participants in 19 clinical trials were included. Of these trials, nine tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/day (median 400 IU/day). Nine of 11 trials testing high-dosage vitamin E (≥ 400 IU/day) showed increased risk (risk difference > 0) for all-cause mortality in comparisons of vitamin E vs. control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10 000 persons. For low-dosage vitamin E trials, the risk difference was −16 per 10 000 persons. A dose–response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/day.