Aim: Radiotherapy plays a significant role in the management of head and neck cancers. However, mucositis and xerostomia are the most common side effects in curative treatment. The aim of this prospective, randomized study is to compare the efficacy of zinc sulphate and amifostine in preventation of radiation induced salivary gland damage in head and neck cancer (HNC) patients using quantitative salivary gland scintigraphy (QSGS). Patients and Methods: Thirty patients with HNC who had received radio±chemotherapy were randomly assigned to receive either zinc sulfate or amifostine. All the patients were once a week during RT for oral mucositis using the Radiation Therapy Oncology Group (RTOG) Acute Radiation Morbidity Scoring criteria, and measurement of body weight. Before and 2 months after treatment, salivary gland scintigraphy was performed. Using the time–activity curves, changes in the maximum uptake (UR) and relative saliva excretion rate (ER) between pre- and post- treatment were calculated. The measurements were statistically compared using paired Mann-Whitney U test. Statistical significance was defined as p < 0.05. Results: The protective effect of zinc sulphate on the salivary glands was similar to amifostine and there were no statistically significant difference in UR, ER results at QSGS, oral mucositis or weight loss between the two groups. Conclusion: The effectiveness of both support therapy was compared and there was no significant difference in efficacy. However, because of the cost difference, the use of the zinc sulphate can be an alternative to amifostine for prevention of xerostomia, oral mucositis and other toxic effects. Further studies with more patients and follow-up are suggested in this regard.