The administration of methylprednisolone (MP) (2.125-4.125 G) To the cryoprecipitated plasma perfusate of 41 canine kidneys preserved with hypothermic pulsatile perfusion is associated with increased vascular resistance, decreased plasma flow, and rising perfusion pressure that become more pronounced over periods up to 20 hr. The magnitude of the increase in renal resistance is directly related in a bimodal fashion to the dose of MP and to the interval following drug administration. The increase in renal resistance is generally irreversible (three or four cases) under conditions of high MP dosage (2.125 g) administered for 4 hr or longer. Severe histological changes occurred in kidneys perfused with MP 20 hr or longer. These changes were primarily glomerular changes consisting of necrosis of capillary loops, occlusion of Bowman's space, basement membrane thickening, and endothelial cell damage; tubular changes consisting of occlusion of tubular lumens and tubular epithelial cell damage; and arteriolar changes consisting of occlusion primarily of afferent arterioles with dense eosinophilic material. These studies demonstrate that the administration of high doses of MP can produce irreversible hemodynamic and histological changes in the isolated, perfused kidney and may preclude its use in pretreating kidneys for transplantation.