The purpose of this study was to test two novel antioxidant drugs, each capable of inhibiting membrane peroxidation and of free radical scavenging, as topical radioprotectants for the intestine. A loop of rat midintestine was exteriorized and radiated while the remainder of the animal was protected in a lead box. The intestine was first compartmentalized and each segment filled with a test solution. Radiated segments of intestine were compared, drug filled with vehicle filled, and both with normal unradiated intestine. The animals were killed 5 days after 1100 cGy radiation to the exteriorized loop. Crypt numbers and mucosal height were used as the measures of injury protection. On the basis of crypt numbers, the 21-amino steroid (U-74500A) gave approximately 40% and the vitamin E-like compound (U-78518F) gave 60% reduction in crypt loss. The authors conclude that lumenal antioxidant drugs can provide partial protection of the intestinal mucosa from acute radiation damage and that these two specific agents are effective and potentially useful.