The appearance of an I131-labeled plasma protein substitute, polyvinylpyrrolidone (PVP), in the gastrointestinal tract was increased following X-irradiation or nitrogen mustard treatment of rats. Previous work suggests that leakage of PVP into the intestine may be used as an index of capillary permeability to large molecules. On this basis radiation and nitrogen mustard appear to act by a common mechanism on vascular permeability, as indicated by the similarity in the magnitude and duration of response to them. Partial-body irradiation showed that the upper small intestine was probably the principle site of leakage, and that the effect was caused by direct action on the intestinal epithelium. It was not caused by an increased excretion in the bile nor by an accumulation of secretions which were not reabsorbed because of impaired mucosal function. Treatment of X-irradiated animals with hesperidin-ascorbic acid, diisopropylfluorophosphate, or serotonin had no effect on PVP excretion but prophylactic administration of cysteine did decrease leakage.