Objective: The radioprotective effects of amifostine remain uncertain in patients with nasopharyngeal carcinoma (NPC), and adverse effects and cost limit generalization of its classical everyday regimen. This phase II multicenter randomized controlled trial aimed to explore whether amifostine could ameliorate the toxicities of NPC patients in the era of intensity-modulated radiotherapy (IMRT), and to compare different regimens of amifostine on effectiveness and safety. Methods: Patients with stage I-IVB NPC were involved prospectively from January 1st, 2013. All patients received radical treatment based on IMRT. After a randomization stratified by their stage, these patients were allocated into 3 groups: the group treated without amifostine, the group treated with the everyday regimen of amifostine, and the group treated with the every-other-day regimen. The 3 groups of patients were compared on radiotherapy-related acute toxicities, treatment effects of NPC, and amifostine-related complications. Results: Until August 31st, 2017, totally 187 patients completed experimental intervention. Only amifostine of everyday regimen appeared to reduce the patient proportion of mucositis (79.1% vs. 96.8%, P=0.002). Hypocalcemia was less common in patients treated without amifostine than in those treated with amifostine (22.6% vs. 53.4% vs. 41.8%, P=0.002). Neither complete remission rates nor the survivals were affected by amifostine. Conclusions: Amifostine of everyday regimen could reduce mucositis in NPC patients who received IMRT, though it also had the possibility to cause more hypocalcemia.