Background: To assess the efficacy of immunonutrition on severe radiotherapy-induced mucositis (RIOM) during concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC). Methods: In total, 30 patients with NPC undergoing CCRT were enrolled in our study. Patients in immunonutrition group (n = 15) receive an immunonutrient formula containing omega-3-fatty acids, arginine, nucleotides from five days before radiotherapy until the end of radiotherapy. Patients in control group (n = 15) receive isocaloric isonitrogenous product. The incidence of grade 3 or 4 RIOM was compared between two groups. Results: Although there was no difference of the incidence of grade 3-4 oral mucositis between the two groups (p = 0.050), the rate of severe mucositis were 13.3% (2/15) in immunonutrients, which was much lower than 53.33% (8/15) in control group. A significant improvement in body fat mass was observed in immunonutrition group than that in control group during the CCRT (3.476, 95CI% 0.015~6.937, P = 0.049) and at the end of CCRT (4.115, 95%CI 0.872~7.359, p = 0.015). And the levels of interleukin 6 (-6.765, 95%CI -16.104~2.573, p = 0.148) and C-reactive protein (CRP) (-7.937, 95%CI -20.395~4.520, p = 0.201) at the end of radiotherapy were lower in immunonutritions even though no statistical difference was reached. In addition, immunonutrition has the potential to improve the life of the patient in the EORTC QLQ-H&N35 scales in painkillers (-13.332, 95%CI -22.612~-4.052, p = 0.007), pain (-15.873, 95%CI -32.131~0.384, p = 0.055), dysphagia (-15.516, 95%CI -34.136~3.104, p = 0.099) and dry mouth (-12.860, 95%CI -31.135~5.415, p = 0.160) at the end of radiotherapy. No patients died of treatment-related causes. Conclusions: Our study indicates that immunonutrition may reduce severe oral mucositis and improved quality of life for patients with NPC during CCRT. Further studies with a larger sample size on the role of immunonutrition in oral mucositis are required to substantiate the result of the study.