Background: Oropharyngeal mucositis is a common toxicity seen in patients with HNSCC on concurrent chemoradiation (CTRT). Oral cryotherapy is effective in preventing oral mucositis in patients on 5FU-based therapy. The effect of oral cryotherapy on mucositis in patients with HNSCC receiving CTRT is not known. Hence, we conducted this study to assess the efficacy of oral cryotherapy. Methods: This was an open-label, randomized study that included adults with HNSCC on adjuvant/radical CTRT, an ECOG PS 0-2, without baseline mucositis or contraindications to oral intake. The patients were randomized 1:1 to the oral cryotherapy (CRYO) arm or control (CONT) arm. All patients in the CRYO arm received oral cryotherapy in the form of ice chips within the first 5 fractions of radiotherapy (RT), and till the end of CTRT or till the development of grade 3 or higher mucositis. Patients were asked to keep ice chips in the mouth, 30 minutes before the start of RT. Once the ice melted, they were asked to swirl the melted ice water in their mouth and gargle with it before swallowing/spitting it. This procedure was repeated for 20-30 minutes until the start of RT and for 10 minutes after RT for the day. The same procedure was followed during chemotherapy (CT) infusion, on other days this procedure was repeated 5-7 times/day. Patients in the CONT arm received CTRT and toxicities were managed as per the institutional standards. Patients were evaluated for mucositis and other toxicities of CTRT (CTCAEv5.0) at baseline and weekly intervals during CTRT and at the first follow-up visit 10-12 weeks after completion of CTRT. The primary endpoint was the incidence of grade 3-5 mucositis at any time during CTRT and up to 3 months after completion. Secondary endpoints were QoL and compliance. Descriptive statistics were performed. The incidence of grade 3 or higher mucositis and other toxicities were compared between the arms using the Chi-Square test. Results: 128 patients were enrolled in the study, 64 in each arm. The median age was 59 years (IQR 40-58.75). Most of the patients were males, 93.75% and 85.9% in the CRYO and CONT arms respectively. Most of the patients had ECOG PS 1, 65.6% and 68.75 % in the CRYO and CONT arm respectively. Most patients (40/64, 62.5%) in both arms received concurrent cisplatin as the radiosensitizer. More patients in the CONT arm (23/64 patients, 35.9%) developed grade 3 or higher mucositis as compared to the CRYO arm (17/64 patients, 26,6%), but this was not statistically significant (p=.340). There was no statistically significant difference in the incidence of grade 3 or higher dysphagia, anemia, neutropenia, rise in creatinine, hyponatremia, or radiation dermatitis between the 2 arms. There were no new safety signals noted with the use of cryotherapy. Conclusions: Although cryotherapy reduced the incidence of grade 3-5 mucositis, it was not significant and its efficacy was not established. Clinical trial information: CTRI/2020/07/026657.