Statement of the Problem: A significant proportion of patients undergoing chemotherapy or radiotherapy suffer from mucositis. The first symptom of oral mucositis is pain. Severe pain, burning sensation, and discomfort in the oral cavity make it difficult to continue treatment and even continue living in these patients.Purpose: The aim of this study was to evaluate and compare the effect of amitriptyline mouthwash (in two forms of simple and niosomal) as a local anesthetic agent with benzydamine HCl mouthwash in oral mucositis after radiotherapy or chemotherapy.Materials and Method: This double-blind study was performed on 60 patients with oral mucositis caused by radiotherapy and chemotherapy. The severity of mucositis was determined based on patient judgment; then dental examination was performed and recorded in a checklist. Three groups were assigned based on using either benzydamine HCL, amitriptyline, or niosomal form of amitriptyline. Pain and burning sensation were evaluated with VAS at different time intervals: before use and one, five, ten, and thirty minutes and one hour after using mouthwash. T-test was used to compare the intensity of pain between the two groups. ANOVA and Tukey test were used to compare the intensity of pain between groups.Results: Statistical analyses showed the maximum reduction in pain intensity at two different time intervals (p= 0.04). Ten minutes after the use of niosomal form of amitriptyline, a 95% decrease in pain was observed. A 99% reduction in pain occurred after the use of simple form of amitriptyline (p= 0.04).Conclusion: Use of amitriptyline mouthwash had local anesthetic effects in oral mucositis without systemic side effects. Decrease in the severity of pain with the use of amitriptyline mouthwash was more than that of benzydamine HCL mouthwash. Keywords ● Amitriptyline  ● Benzydamine Mucositis  ● Topical anesthetic  ● Mouthwash