Concurrent chemotherapy and radiation are usually indicated for locally advanced carcinomas such as head and neck and anal malignancies. Because of the toxicity of the treatment, patient selection plays an important role in recommendations to treat with a curative intent. Elderly patients (> 70 years), those with underlying medical conditions or acquired immunological disorders (AIDS) are commonly excluded from combined modality therapy because of their perceived inability to tolerate the aggressive treatment. They may thus be deprived of a potentially curative therapy. In an attempt to improve outcome, we conducted a pilot study using amifostine, a radioprotector, to increase the tolerance of such compromised individuals to treatment. Amifostine (500 mg intravenously) was given during chemotherapy on days 1-5, and days 21-25 of radiation regimen. All patients were able to complete the chemoradiation. Despite the locally advanced stage of the disease, five out of our six patients achieved a complete response (CR). One patient with synchronous primaries had a complete response for the base of tongue cancer and regression of the esophageal cancer, which allowed him to resume oral feeding. All patients achieved improved quality of life. Successful chemoradiation appears to be feasible in patients with advanced stage, age and/or underlying medical conditions when amifostine is integrated in the treatment.