Twenty-five opossums (Didelphis virginiana) were evaluated before irradiation by fiberoptic endoscopy and air-contrast barium esophagram examination. All animals received 2250 rad 60Co-irradiation in a single exposure to the entire esophagus and lower exophageal sphincter. Animals received treatment with indomethacin before and daily for 1 wk postirradiation of 16, 16-dimethylprostaglandin E2 before irradiation and every 4 hr for 24 hr postirradiation. Control animals received only injection vehicle. Acute esophagitis occurred 7--10 days postirradiation in control animals and was characterized by erythema, ulceration, and sloughing of esophageal mucosa as determined by air-contrast barium esophagram, endoscopy, and histology. Prostaglandin-treated animals showed more severe evidence of esophagitis than control animals. Indomethacin-treated animals showed no signs or only mild esophagitis posttreatment. It is concluded that indomethacin treatment may significantly reduce the severity of radiation esophagitis perhaps by blockade of prostaglandin synthesis.