Amifostine (Ethyol) has been evaluated clinically as a radioprotective agent for the prevention of xerostomia and mucositis for patients receiving radiotherapy (RT). Currently, amifostine is approved for the prevention of xerostomia in head and neck cancer patients receiving RT when administered intravenously (IV) before RT. For the clinician, there would be several advantages to administering the drug subcutaneously and to being able to show its protective effects on mucositis. The authors have developed a rat RT model to examine the protective effects of amifostine after IV and subcutaneous (SC) administration in a mucositis model. Rats (5 per group) were given 200 mg/kg (human dose equivalent of approximately 1,300 mg/m(2)) of amifostine either IV or SC, and their head and neck regions were exposed to 15.3 Gy of gamma radiation 0.5, 2, 4, and 8 hours after amifostine administration. For 10 days after treatment, the oral cavities of the rats were examined for signs of mucositis. Mucosal erythema and mucosal edema were scored according to 0 through 5 and 0 through 2 scales, respectively, with the scores added to indicate overall mucositis. The average mucositis score for the untreated animals was 3.5. Rats were protected from mucositis up to 4 hours when given amifostine either IV or SC. Rats that received amifostine SC, but not IV, were protected from mucositis 8 hours after administration. Preliminary pharmacokinetic data have revealed slightly higher active metabolite (WR-1065) levels in the parotid gland and small intestine in the rats given amifostine SC compared with IV and equivalent levels in the plasma and kidney. The data showed that SC administration of amifostine gave radioprotection comparable to IV administration up to 4 hours before RT and may be more effective than IV administration at longer pretreatment intervals.