Symptoms related to salivary gland damage are one of the most frustrating complications after radioactive iodine (¹³¹I) therapy. To the best of our knowledge, this is the first study that aimed to evaluate the prophylactic effect of Bethanechol on the radioiodine content of salivary gland. Fifty patients who were referred to ¹³¹I therapy were randomized into Bethanechol and placebo groups. Patients received Bethanechol or Placebo (25 mg, 2 times daily), starting 2 h after ¹³¹I therapy to 1-month.  Both groups were compared at baseline, 10, 30 and 90 days after ¹³¹I therapy based on the following: symptoms related to salivary gland damage; unstimulated whole saliva (UWS) and quality of life using University of Washington Quality of Life 4 questionnaire. Bethanechol group presented significantly lower complaints of dry mouth on 10 (p = 0.047) and 30 (p = 0.003) days compared with placebo. Salivary gland pain and swelling were more frequent among placebo patients at 10 days (p = 0.047). Comparison of the two groups by UWS, no statistical difference was found. Placebo group presented worse score related to activity (p = 0.034), saliva (p = 0.05) and humor (p = 0.05) at 10 days; palate (p = 0.05) and saliva (p = 0.05) at 1 month. Interestingly, Bethanechol patients who received ¹³¹I dose > 125mCi, showed better xerostomia indices when compared to the Placebo with same dose. Bethanechol during ¹³¹I therapy was found to be effective in decreasing the acute salivary gland damage with impact on patients' quality of life.