Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non-statistically significant increases in total mortality. The purpose of this project was to perform a meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality by using data from RCTs. A total of 135 967 participants in 19 clinical trials were eligible. 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 the 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 (95% CI 3 to 74 per 10 000 persons; P = 0.035). For low-dosage vitamin E trials, the risk difference was −16 per 10 000 persons (CI −41 to 10 per 10 000 persons; P > 0.2). 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.