It has been suggested that salt loading protects against amphotericin B-induced nephrotoxicity. The influence of saline loading on the nephrotoxic response to amphotericin B (50 mg/dose given i.v. over 4 hr 3 ×/week for 10 weeks) was assessed in two groups often patients each who were diagnosed with mucocutaneous leishmaniasis. Patients were randomized to receive either 1 liter of 0.9% saline or 1 liter of 5% dextrose in water, administered i.v. over one hour in a double-blinded manner, directly prior to amphotericin B administration. Renal function was monitored on a weekly basis two days after the last dose of amphotericin B. Baseline characteristics were similar in both groups except for a slightly higher serum creatinine concentration (Cr) in the saline group (0.8 ± 0.05 vs. 0.6 ± 0.04 mg/dl). Baseline sodium (Na) excretion was relatively high (262 ± 23 mmol/day in the dextrose group and 224 ± 17 mmol/day in the saline group). None of the patients sustained an increase in Cr to values greater than 1.7 mg/dl. Although mean Cr remained within normal, there was a significant difference between the two groups over the ten week period, with the dextrose group sustaining a significant increase in Cr and the saline group remaining unchanged. Serum potassium (K) levels fell in both groups necessitating oral K supplementation. The saline group required significantly greater amounts of K supplementation to maintain a normal serum K. Amphotericin B caused a rapid reduction in the acidification ability of the kidney in response to an ammonium chloride load. Under these conditions, the saline group had a poorer ability to acidify the urine. Urine volumes were not different between the two groups, and the specific gravity of the urine sustained a significant and similar decrease in the two groups. Neither plasma trough amphotericin B levels nor tissue concentrations at the site of the lesion were different between the two groups, suggesting that the effect of salt is probably not on the basis of pharmacokinetic changes. This study supports the hypothesis that salt loading confers protection against reductions in renal function by amphotericin B, but does so at the expense of enhancing K loss. The lower overall incidence of nephrotoxicity in comparison to prior published experience could be due to racial variation in responsiveness, the high baseline salt intake, or lack of coadministration of other nephrotoxic drugs.