The effect of isoosmolar volume reduction on plasma ADH level was studied in 8 patients with chronic renal failure utilizing hemofiltration technique. Plasma ADH fell significantly (P less than 0.001) after one hour of hemofiltration despite volume reduction which was expected to elevate the ADH level. After two hours of hemofiltration, ADH remained low in 5 patients and increased in 3. Post-hemofiltration mean blood pressure was generally lower in patients whose ADH rose than those whose ADH remained low. The two groups were otherwise comparable with respect to total fluid loss, hemofiltration rate, and fluid removed expressed as percent body weight. It can thus be suggested that in these patients a rise in plasma ADH in response to fluid reduction may require a fall in the arterial blood pressure below a critical level. While the rise in plasma ADH observed with continued fluid removal in some patients can be readily explained, we have no clear explanation for the paradoxical initial fall of ADH in all patients and subsequent maintenance of low levels observed in the majority of patients. This unusual ADH response to isoosmolar volume reduction may represent some unidentified mechanism of ADH regulation in patients with end-stage renal disease.