Treatment with amphotericin B deoxycholate (AB) is associated with dose-related nephrotoxicity. We conducted an open and randomized trial to evaluate the efficacy of an oral rehydration solution (ORS) to prevent nephrotoxicity of AB, compared with an intravenous saline solution (SS). Adult patients with mucosal leishmaniasis in whom AB was indicated received either three liters or ORS or one liter of SS. Renal function tests were performed at baseline and during treatment. Forty-eight patients were included (ORS = 25, SS = 23). No difference was observed in serum creatinine, creatinine clearance, serum urea, and serum sodium values during treatment, but serum potassium values were lower in the SS group than in the ORS group (P < 0.03). Treatment was more temporarily discontinued in the SS group than in the ORS group (7 patients versus 1 patient, P = 0.02). We conclude that ORS is comparable to SS in preventing glomerular damage of AB, but more effective in preventing hypokalemia. Copyright © 2006 by The American Society of Tropical Medicine and Hygiene.