Tubular obstruction is an important pathophysiologic mechanism in acute renal failure (ARF). The anatomic basis for this obstruction may be impaction of the pars recta of the proximal tubule with sloughed brush border debris. If so, then diuretics which act proximal to the site of obstruction (e.g. mannitol, M) should be more effective in expelling brush border debris from the tubules than diuretics with more distal sites of action (e.g. furosemide, F). This difference could make M superior to F as a protector of renal function following acute renal injury. To test this hypothesis 35 rats were subjected to M or F diuresis. After a 60-min control period, nephrotoxic (HgCl2) or ischemic (vascular cross-clamping) ARF was induced. Glomerular filtration rate (GFR; clearance iothalamate-125I) and the urinary excretion of brush border derived-renal tubular epithelial antigens (RTE; measured by RIA) were determined before and after the nephrotoxic and ischemic insults. During control periods of diuresis, M and F produced comparable urine flow rates, GFRs, and RTE excretion. However, following HgCl2 or renal ischemia, M-treated rats had 3 times (HgCl2) and 9 times (ischemia) greater RTE excretion rates than did their F-treated counterparts (p < 0.01–0.001). M-treated rats also retained one third more of their original GFRs than did the F-treated rats (p < 0.01). The beneficial effects of M did not require its administration prior to renal injury: a single M bolus immediately post-ischemia produced GFRs and RTE excretion rates comparable to those observed in rats which had received M prophylactically. Conclusion: M is superior to F in protecting against ischemic and HgCl2 induced ARF. The efficacy of M may be due, in part, to its proximal tubular site of action which facilitates flushing of the pars recta of brush border debris, thereby decreasing intratubular obstructio