There has been concern that long-term supplementation with high-dose antioxidant vitamins, especially vitamin E (α-tocopherol), may increase all-cause mortality. We conducted a randomized controlled trial with α-tocopherol (400 IU/day) and β-carotene (30 mg/day) supplements among 540 head and neck cancer patients treated by radiation therapy. Supplementation with β-carotene was discontinued during the trial. The supplements were given during radiation therapy and for 3 additional years. During the follow-up (median 6.5 years), 179 deaths were recorded. All death certificates were obtained. All-cause and cause-specific mortality rates were compared between the 2 arms of the trial by Cox regression. All-cause mortality was significantly increased in the supplement arm: hazard ratio: 1.38, 95% confidence interval 1.03–1.85. Cause-specific mortality rates tended to be higher in the supplement arm than in the placebo arm. Our results concur with previous reports to suggest that high-dose vitamin E could be harmful. © 2006 Wiley-Liss, Inc.