Probucol is a lipid-regulating drug that also has antioxidant properties, This study was designed to test the possibility that probucol could provide radioprotection of the intestine when administered either intralumenally or systemically. Tissue damage was evaluated histologically by quantifying the number of crypts per circumference and the mucosal height. Animals were sacrificed 5 days after 11 Gy of X irradiation. In one series of experiments, a loop of mid small bowel was exteriorized operatively and compartmentalized into segments, each filled with probucol or saline. Intralumenal administration of probucol prior to irradiation led to a significantly greater number of crypts per circumference and mucosal height compared to saline-filled irradiated controls. In another series of experiments, five groups of rats were irradiated: (1) probucol in the small bowel lumen, (2) intravenous probucol, (3) probucol by gavage, (4) probucol added to standard rat chow and (5) saline control. In the rats given probucol intravenously prior to X irradiation, crypt numbers and mucosal height were significantly enhanced. Probucol given by garage also resulted in protection. Rats fed a diet containing probucol showed no significant protection. Topical administration was more effective than systemic. Probucol protects the intestinal mucosa from acute radiation damage when given topically, intravenously or by gavage, but does not do so when given as a dietary supplement.