We directly assessed the efficacy of vitamin E supplements for primary prevention of type 2 diabetes among apparently healthy women in the Women's Health Study randomized trial. Between 1992 and 2004, 38,716 apparently healthy U.S. women aged >or=45 years and free of diabetes, cancer, and cardiovascular disease were in two randomly assigned intervention groups and received 600 IU of vitamin E (alpha-tocopherol, n = 19,347) or placebo (n = 19,369) on alternate days. During a median 10-year follow-up, there were 827 cases of incident type 2 diabetes in the vitamin E group and 869 in the placebo group, a nonsignificant 5% risk reduction (relative risk [RR] 0.95 [95% CI 0.87-1.05], P = 0.31). There was no evidence that diabetes risk factors including age, BMI, postmenopausal hormone use, multivitamin use, physical activity, alcohol intake, and smoking status modified the effect of vitamin E on the risk of type 2 diabetes. In a sensitivity analysis taking compliance into account, women in the vitamin E group had an RR of 0.93 (95% CI 0.83-1.04) (P = 0.21) compared with those randomized to placebo. In this large trial with 10-year follow-up, alternate-day doses of 600 IU vitamin E provided no significant benefit for type 2 diabetes in initially healthy women.