Irradiation can have a profound effect on intestinal motor activity. Previous studies have suggested that prostaglandins may play some role in radiation-induced enteritis. The present study investigated the effects of abdominal X-irradiation with or without indomethacin treatment on jejunal myoelectric activity and prostaglandin synthesis by measuring the prostaglandin content of mesenteric arterial and venous plasma and in the intestinal lumen in dogs. After X-irradiation, venous concentrations and arteriovenous concentration differences of prostaglandin (PG)E2, PGF2 alpha, and 6-keto-PGF1 alpha increased markedly. The increased venous concentrations were in part attributable to increased mucosal and/or submucosal synthesis by inference from increased concentrations of these metabolites assayed from the jejunal lumen. Irradiation produced histological damage to the mucosa and submucosa and abnormalities in the migrating motor complex, jejunal slow waves, and a decrease in spike burst activity. Inhibition of prostaglandin synthesis by treating the animals with indomethacin reduced the severity of illness, the histological injury, and changes in myoelectric activity induced by irradiation. Such treatment should be evaluated further to treat patients exposed to large doses of irradiation.