Background: Vitamin D was found to have potent antioxidant effect and play an important role in activating the dendritic cells, macrophages, and monocytes, as well as stimulating DNA damage repair suggesting its role in reducing the incidence of radiation induced oral mucositis and other acute side effects. Objective: To evaluate impact of vitamin D administration on radiation induced oral mucositis and other radiotherapy related toxicity and to assess its effect on response to treatment. Patients and methods: This is a prospective case-control study conducted on sixty-one patients diagnosed as head and neck cancer that would receive radiotherapy either as definitive or adjuvant treatment at Clinical Oncology and Nuclear Medicine Department, Menoufia University. Two groups of patients; vitamin D group whom vitamin D was prescribed and control group without vitamin D. All the patients were examined clinically weekly after the start of radiotherapy for WHO mucositis score. Results: Vitamin D supplementation reduced oral mucositis in head and neck cancer patients receiving radiotherapy with or without chemotherapy with significant improved oral mucositis in vitamin D arm, p value <0.001in weeks two, three, four, five and six. Also, skin toxicity, taste changes and dysphagia were significantly better in vitamin D arm, p value at week one, two, three, four, five were 0.011, 0.041, 0.001, <0.001, 0.003 respectively, with higher incidence of xerostomia in vitamin D arm in weeks six and seven however no significant differences between two arms. Conclusion: This study demonstrates that vitamin D administration had beneficial effect on reducing oral mucositis and other complications like skin toxicity, taste changes and dysphagia during radiotherapy treatment in head and neck cancer patients, it helps in the reduction of the chance of treatment interruption and improved response to radiation treatment.