There have been anecdotal reports describing patients with systemic lupus erythematosus (SLE) and inappropriately elevated secretion of antidiuretic hormone (ADH), but no systematic studies of ADH and its metabolism in SLE have been performed. We measured plasma ADH levels in 36 stable SLE patients with normal renal function and examined the relationship of the circulating ADH concentration to clinical disease activity and effective extracellular fluid volume as reflected by peripheral plasma renin activity (PRA) and plasma aldosterone concentration. The mean ADH level was elevated, 11.4 ± 1.0 μU/ml (normal 0.4–1.4 μU/ml), while mean PRA and aldosterone were 5.4 ± 0.6 ng/ml/h and 10.6 ± 1.6 ng/l00 ml, respectively. When patients were divided into two groups according to disease duration, those with SLE for 2 years or more had significantly higher plasma ADH levels (13.9 ± 1.4 vs. 7.7 ± 0.9 μU/ml; p < 0.001 and urinary osmolality (697 ± 63 vs. 445 ± 49 mosm/kg; p < 0.02) compared to those with SLE of less than 2 years duration. No differences in serum Na + , K+, PRA, plasma aldosterone concentration, C3, or 24-hour urinary protein excretion were noted between these two groups. Six patients with SLE for less than 2 years underwent a standard water load (20 ml/kg); in 3/6 there was a paradoxical increase in the plasma ADH concentration. These findings indicate that SLE is associated with elevated plasma ADH levels that increase with prolonged disease duration. This abnormality is unrelated to the usual serologic indices of SLE activity, effective extracellular fluid volume status, or any apparent renal unresponsiveness to ADH. We therefore suggest that in patients with SLE, there exists a state of primary neurohypophyseal hypersecretion of ADH. This hypothesis is supported by the abnormal ADH secretory response in 3/6 patients who were given a free water load.