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The present study was conducted to determine the preventive efficacy of vitamin C/E complex supplementation for radiotherapy (RT)–induced xerostomia in patients with head and neck cancer.Prospective, double-blinded, randomized, placebo-controlled study.A single tertiary referral institution.The trial group (n = 25) received antioxidant supplements (100 IU of vitamin E + 500 mg of vitamin C) twice per day during RT, while the control group (n = 20) received an identical placebo. Pre-RT and 1 and 6 months post-RT, patient-reported xerostomia questionnaires, observer-rated xerostomia score, and salivary scintigraphy were serially obtained to compare xerostomia severity between the 2 groups.The trial group showed greater improvements in xerostomia questionnaire and score at 6 months post-RT when compared with those at 1 month post-RT (P = .007 and .008, respectively). In contrast, the control group showed no changes between 1 and 6 months post-RT. By salivary scintigraphy, there was no difference in maximal accumulation or ejection fraction between the 2 groups. However, the trial group maintained significantly better oral indices at the prestimulatory (P = .01) and poststimulatory (P = .009) stages at 1 month post-RT, compared with the control group. At the final follow-up, there was no difference in overall survival and disease-free survival between the 2 groups.Our data suggest that short-term supplementation with an antioxidant vitamin E/C complex exerts a protective effect against RT-induced xerostomia.