The effectiveness of plasma infusion, saline injection, mannitol infusion and combined treatment with mannitol and saline in modifying the development of glycerol-induced hemoglobinuric acute renal failure was studied in the rat. All modes of therapy decreased the severity of azotemia considerably, and combined treatment with mannitol and saline almost totally prevented the development of azotemia. The intrarenal effects of prophylactic treatment on individual nephron function were studied by micropuncture techniques. Function of the best nephrons was comparable in all therapeutic groups, the degree of renal insufficiency in each group being a manifestation of the proportion of those nephrons which had only moderately diminished function. The effectiveness of each agent correlated with the prevention of severe renal ischemia shortly after glycerol injection. Their ability to modify GFR in dehydrated control rats did not correlate well with the degree of protection afforded after glycerol injection. Improvement in extracellular fluid volume was not the prime feature associated with protection from azotemia.