To investigate the clinical effect of Compound Kushen Injection(CKI) on radiation-induced injury in head and neck cancer(HNC) patients and the safety.Methods:A multicenter open-label randomized controlled trial was conducted.Adults with HNC were randomized into the control group(n=100) and treatment group(n=100).The treatment group received CKI and radiotherapy(RT)/chemoradiotherapy(CRT) and the control group was treated by RT or CRT alone.The primary outcome indicators were the incidence and severity of radiation-induced skin injury and radiation-induced oral mucositis.Secondary outcome indicators were quality of life and efficacy on the solid tumor.The safety of CKI was evaluated with Common Terminology Criteria for Adverse Events(CTCAE) Version 4.0.Results:Compared with control group，the treatment group had low incidence of skin injury≥grade 2(P<0.05) and low incidence of oral mucositis≥grade 2(P>0.05).The treatment group showed a better change in physical functioning，social functioning，fatigue，pain，constipation，financial difficulty，and overall symptom scales compared with the control group from baseline to the end of RT(P<0.05).The incidence of adverse events showed no significant difference between the two groups(P<0.05).Conclusion:CKI has predominant efficacy in reducing the incidence and severity of radiation-induced skin injury，which can improve quality of life and is safe.