Previous studies have demonstrated that the sympathomimetic agent clonidine, administered intravenously immediately prior to injury, provides partial protection against the acute structural and functional impairments associated with experimental ischemic and nephrotoxic ARF. To determine the effect of clonidine, administered orally, on the prolonged course of HgCl2-induced ARF, two groups of rats were studied for a period of 5 days after injury. For 5 days before HgCl2 administration (2 mg/kg s.c.) and throughout the study group I drank water while group II had clonidine (5 mg/L) added to water. The fatality rate was 77% in group I as compared to 11% in group II (p less than 0.001). Renal function (CCr and FENa) was better preserved and recovered more rapidly in group II rats protected with clonidine. Both groups showed varying degrees of proximal tubular cell injury, but group II had significantly fewer necrotic cells and demonstrated earlier evidence of regeneration. Whereas none of the injured cells in the clonidine-pretreated group revealed evidence of calcification, on the second day half the cells of the pars recta in the outer stripe of the medulla were calcified in group I. In group III animals, oral clonidine was started 2 hr after the injection of HgCl2 and also resulted in a significant reduction in fatality rate from 40% in control group to 0% in the clonidine-treated group. In addition, CCr and FENa were better preserved and recovered more rapidly in this group of clonidine-treated rats. These results indicate that oral clonidine, administered either before or shortly after HgCl2-induced ARF, exerts a salutory effect on the course and mortality of ARF by providing protection of renal function and enhancement of the recovery process.