Concurrent chemo-radiotherapy (CCRT) is an ideal treatment for advanced head and neck squamous cell carcinoma (HNSCC). The performance of CCRT induces severe toxicities in HNSCC patients and decreases the quality of life (QOL). Maitake D-Fraction is proteoglycan which has anti-tumor function associated with its immunomodulatory capacity. The polysaccharides of Maitake also have anti-radiation effect in radiation therapy during cancer treatment. This research aimed to illustrate Maitake D-Fraction effects on CCRT-associated adverse events and QOL. During CCRT, Maitake capsules were taken orally 3 times a day, each time 4 capsules, one hour before meals. QOL were analyzed by EORTC QLQ-C30-Chinese version and EORTC QLQ-HandN-35-Chinese version. 141 patients were recruited and divided into an intervention group and a placebo group. Frequencies of severe CCRT-associated adverse events in intervention group were less than in placebo group. Global QOL score in intervention group was higher than in placebo group 5 weeks post treatment. The proportion of patients returning to baseline global QOL score at 6-month was increased by Maitake D-Fraction administration. In conclusion, this randomized clinical trial demonstrated that in advanced laryngeal and pharyngeal cancer patients, the oral administration of Maitake D-Fraction alleviated CCRT-related adverse events and deterioration in QOL.