The mechanism of radiation induced damage to the mucosal lining of the gastrointestinal tract, as well as mucositis, is not fully characterized. Prostaglandins may partially mediate the inflammatory response to radiation damage. The effect of the prostaglandin synthetase inhibitor indomethacin on radiation induced esophagitis, pneumonitis, and tumor response was evaluated in the C3H mouse. The effects of indomethacin on radiation induced damage to the esophagus was determined by evaluation of weigh lost, survival, and histologic findings at doses of 28-34 Gy. Although there is a clear difference that supports the use of indomethacin for the prevention of esophagitis, the radiation dose response for esophagitis is steep and likewise, the therapeutic index for the indomethacin amelioration of radiation esophagitis is narrow. Since the tumor response to radiation is unchanged and since indomethacin clearly lessens radiation induced esophagitis in the mouse, this study suggests that indomethacin should be studied in humans for lessening radiation mucositis without jeopardizing the therapy of tumors.