Acute and long-term oral complications occur in patients receiving mantle radiation therapy or irradiation to the head and neck region for Hodgkin's disease or non-Hodgkin's lymphoma. While considerable data are available on the effect of radiation therapy on the oral function and quality of life of patients with squamous cell carcinoma of the head and neck, such information is lacking for similarly irradiated lymphoma patients. In this article we discuss the rationale and study design of an ongoing, randomized phase II study evaluating the role of amifostine (Ethyol; Medimmune Inc, Gaithersburg, MD) as a radiation protectant in patients receiving head and neck irradiation for lymphoma. Further investigation in this lymphoma population is needed to improve our understanding of the extent of the problem and its impact on patients' daily living and functioning. Importantly, fine-tuning the treatment and management approaches to minimize morbidity while maximizing the survival and quality of life of patients are crucial next steps.