The effect of lithium on the plasma arginine vasopressin (AVP) response to the iv infusion of 5% saline was determined in six patients with primary effective disorder. Lithium did not significantly affect baseline weight, plasma osmolality, sodium, or AVP levels. However, lithium significantly increased the mean rate of change or the sensitivity of the plasma AVP response to the osmotic stimulus (from 0.42 +/- 0.17 to 1.08 to 0.24 pg/ml/mosmol/kg; P less than 0.025, by paired t test). This change was associated with a slight but significant increase in the precision of the response, as reflected in the correlation coefficient, but there was no difference in the calculated intercept or osmotic threshold for AVP secretion. This study indicates that patients on lithium do not, as previously suggested, show partial central diabetes insipidus. Rather, AVP secretion seems to be enhanced. Moreover, the mechanism of this enhancement is a specific increase in the sensitivity of the osmoreceptor rather than a lowering of the osmotic threshold for AVP secretion. The effect of lithium cannot be clearly accounted for by any of the physiological variables known to influence the sensitivity of the system and is probably due to an effect of the drug on the level or activity of neuromodulators which influence the function of hypothalamic osmoreceptors.