BACKGROUND The classic radioprotectant WR-2721 has been shown to reduce the severity of small bowel injury when administered systemically shortly before irradiation is delivered. This study tested the possibility that WR-2721 could provide protection when applied topically to intestinal mucosa. The second question addressed was the influence of pH on the effectiveness of this agent. METHODS The model used involved irradiation of exteriorized rat small bowel. A length of intestine was compartmentalized. The various individual segments were filled with a lumenal Tris buffer (pH 9), WR-2721, or a combination of these two, then irradiated with 1100 cGy. The animals were sacrificed 5 days later. Surviving crypt cells and mucosal height were the criteria used to quantitate mucosal injury. RESULTS The pH 9 buffer alone provided a small (16%) but significant preservation of crypt cell numbers. WR-2721 improved crypt survival by 54% at neutral pH, 83% at pH 9. CONCLUSIONS These data indicate that WR-2721, when applied topically to the small bowel mucosa of the rat before irradiation, provides substantial protection against radiation damage. The degree of benefit is amplified greatly when the drug is in an alkaline medium.