Amifostine (Ethyol; MedImmune Oncology, Gaithersburg, MD) is a radio- and chemoprotective agent currently in clinical use. Based on experimental data showing the potential for mucosal protection and additional information in animal studies showing rapid uptake of amifostine in the salivary glands along with effective radioprotection, several investigators have tested this drug in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The first evidence that amifostine, administered at 200 mg/m(2)/d intravenously before each radiotherapy session, could effectively protect salivary function in patients with HNSCC was provided by McDonald et al in a limited series of HNSCC patients. On the basis of these phase I results, an international multicenter phase III radiotherapy trial with or without amifostine was carried out by Brizel et al in a series of 315 patients with head and neck tumors showing a reduction in xerostomia with no suggestion of tumor protection. Additional data have been obtained in patients with HNSCC regarding the potential protective effect of amifostine on the duration and severity of radio-induced mucositis. This effect was reported in small, randomized studies of patients receiving intensive accelerated radiotherapy (Bourhis et al) or combined radiochemotherapy (Buntzel et al). In conclusion, the experience obtained to date in HNSCC patients treated with radiotherapy supports the selective cytoprotective activity of amifostine to minimize radiation effects while apparently not diminishing tumor control.