Tolerance of the normal rectal mucosa to radiation injury limits the dose that can be safely delivered to the prostate gland with definitive external beam radiation therapy. The radioprotective agent amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) is approved for intravenous use. Laboratory studies indicate that rectal administration results in preferential accumulation of amifostine in the rectal mucosa, and in clinical studies, neither free parent compound nor free active metabolite has been detected in the systemic circulation. This trial evaluates the rates of early and late rectal toxicities in patients with prostate cancer receiving definitive or adjuvant three-dimensional conformal external beam radiation therapy and concurrent daily endorectal applications of amifostine. Endpoints include Radiation Therapy Oncology Group acute and late toxicity gradings, Expanded Prostate Cancer Index Composite self-assessment questionnaires, and proctoscopic examinations with scoring of mucosal damage measured before, during, and after treatment. Eleven patients have been enrolled to date; 10 have completed radiotherapy and three have been followed-up to 6 months. Two patients received 66 Gy to the prostatic bed post-prostatectomy; five patients received 74 Gy and three received 76 Gy to the prostate gland. In all patients, daily fractionation was 2 Gy, and 1 g of amifostine (50 mg/mL in 20 mL reconstituted saline) was administered endorectally 40 minutes before radiation delivery. Daily endorectal administration was well tolerated. To date, six patients have experienced grade 2 (Radiation Therapy Oncology Group) acute toxicities, all but one because of frequent bowel movements relieved by loperamide. The initial trial will proceed until 18 patients are accrued, at which time an interval evaluation of both early and late toxicity endpoints will be conducted.