Radioiodine therapy is known to subject cellular components of salivary glands to oxidative stress leading to salivary gland dysfunction. However, the protective effects of antioxidants on RI-induced SG damage have not been well investigated. The aim of this study was investigated the radioprotective effects of Alpha-lipoic acid (ALA) administered prior to RI therapy in a mouse model of RI sialadenitis. Four-week-old female C57BL/6 mice (n=48) were divided into three groups; a normal control group, a RI-treated group (0.01 mCi/g mouse, orally), and an ALA and RI-treated group. Animals in these groups were divided into 3 subgroups and euthanized at 15, 30, and 90 days post-RI treatment. Salivary flow rates and lag times were measured, and morphologic and histologic examinations and TUNEL assays were performed. Changes in salivary 99mTc pertechnetate uptake and excretion were followed by single-photon emission computed tomography. Salivary lag times and flow rates in the RI + ALA group were faster than in the RI only group. There was no significant intergroup difference in the SG weight. The RI + ALA group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Salivary aquaporin 5 and myoepithelial cells were protected from radiation damage in the RI + ALA group. Low 8-OhdG and high superoxide dismutase 2 immunoreactivity was detected in the RI + ALA group when compared with the RI only group. Fewer apoptotic cells were observed in the RI + ALA compared to the RI only group in the TUNEL assay. The 99mTc pertechnetate excretion level recovered in the ALA group. Pretreatment with ALA before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.