Cytotoxic effects of ionizing radiation on gastrointestinal epithelium may be mediated by oxygen free radicals. Therapeutic intervention directed toward oxidant scavenging and increasing tissue oxygen tension may provide a novel approach to management. We investigated the effects of a nonenzymatic oxygen radical scavenger (vitamin E) and an exogenous PGE1 analog known to increase mucosal blood flow (misoprostol) on acute radiation enteritis. Rats were pretreated with: (1) vitamin E, (2) misoprostol, or (3) a combination of both agents prior to 10 Gy abdominal radiation. Three days following irradiation, net fluid absorption using in vivo isolated loops, mucosal histology, and mucosal morphometry using a computerized videoplan were determined in jejunum, ileum, and colon. Nonirradiated control intestine demonstrated net fluid absorption in all segments, which was not altered by vitamin E and/or misoprostol treatment. Irradiation significantly reduced net fluid absorption in jejunum, ileum, and colon. Vitamin E administered prior to irradiation maintained jejunal, ileal, and colonic fluid absorption near control levels. In contrast misoprostol or a combination of vitamin E and misoprostol did not provide protection against the injury caused by abdominal irradiation. Alterations in intestinal fluid absorption occurred without significant changes in histologic or morphometric appearance. In conclusion, ionizing radiation reduces in vivo intestinal fluid absorption without significant changes in histologic or morphometric appearance. Treatment with vitamin E, but not misoprostol, protects gastrointestinal mucosa against radiation-induced absorptive injury.