To improve the resectability and long-term local control of locally advanced rectal cancer, we have initiated a radiation dose-escalation trial. It is hoped that the radioprotector amifostine will sufficiently reduce rectal morbidity (without also reducing tumor response) to permit increasing radiation doses. Only 6 patients have been treated at the first dose level (45 Gy with a 9-Gy boost and concurrent continuous infusion of 5-fluorouracil). During treatment, daily stool frequency improved or was stable. There was one case of transitory severe proctitis/enteritis. Four of the six patients achieved objective responses to preoperative treatment. These very early results suggest that the use of amifostine does not interfere with tumor response and that it may facilitate the delivery of higher boost doses to the rectum.