Ten patients with amyotrophic lateral sclerosis were treated during 5 consecutive days with intravenous infusion of high-dose human leukocyte interferon-α (IFN-α) or placebo in a single-blinded randomized trial. To assess the effect of IFN on the water and electrolyte balance, serum electrolytes, creatinine, and antidiuretic hormone as well as urine excretion of electrolytes, aldosterone, and cortisol were measured before the trial and during the fourth day of IFN infusion. Compared with placebo the results showed a significant reduction of the mean serum calcium level (from 2.28 ± 0.03 mmole/liter to 2.01 ± 0.06 mmole/liter; p < 0.01), that of the mean serum osmolality (from 296 ± 9.9 mosm/ kgH2O to 281 ± 2.5 mosm/kgH2O; p < 0.05) and that of the mean urinary excretion of magnesium (from 5.32 ± 2.04 mmoles/liter to 2.65 ± 1.68 mmoles/liter; p < 0.05). Careful observation of water and electrolyte balance is emphasized during high-dose IFN treatment. © 1990, Mary Ann Liebert, Inc. All rights reserved.