Background: Oral mucositis is a feared complication of radiation therapy of head and neck cancers, causing severe pain that affects oral functioning, nutrition, and quality of life, as well as therapy non-adherence or failure. Growing reports suggested that methylene blue (MB) oral-rinse was an effective and safe treatment for this oral pain. Methods: In order to evaluate the efficacy and safety of MB oral-rinse for the treatment of oral pain from mucositis in patients treated with radiation therapy of head/neck, we retrospectively evaluated patients who experienced refractory pain despite conventional therapy. Results: We identified 58 patients who received MB oral-rinse. Most were receiving treatment for squamous cell carcinoma of the tongue (n = 26, 44.83%) and squamous cell carcinoma of the tonsil (n = 14, 24.1%). The most common cancer therapy used was chemotherapy plus radiation (n = 23, 39.66%). The median duration of symptoms was 14 days. The mean NRS pain score before MB oral-rinse therapy was 7.59 (±1.68 standard deviation [SD]; median 8), and after therapy, 2.05 (±2.20 SD; median 2) (P< 0.0001). The mean oral function scores (ability to talk, chew, and swallow) before MB oral-rinse therapy was 3.55 (±1.33 standard deviation [SD]; median 3.5), and after therapy, 0.52 (±0.86 SD; median 0) (P < 0.0001). Among 58 patients, n = 11; 18.92% had percutaneous feeding tubes placed before using MB oral rinse. Of those, four (36%) were soon removed after pain was controlled using MB. A few patients had PEG tubes inserted despite using MB oral rinse (n = 2; 3.44%), one for malnourishment and another for dehydration. Few adverse events were reported (n = 9, 15.48%) Three patients experienced oral burning sensation during the first-time use. One patient discontinued MB oral-rinse use due to cost of pharmacy compounding charge. Other discontinued it for unknown reason. Conclusions: MB oral-rinse is an effective and safe treatment for refractory pain from oral mucositis related to radiation therapy.