The effect of blood volume on the osmotic control of the antidiuretic hormone, arginine vasopressin (AVP), has been studied in 18 healthy young adults. Changes in blood osmolality and/or volume were produced by each of 3 procedures--fluid deprivation, orthostasis, and hypertonic saline infusion--and the resultant changes in plasma AVP were measured by radioimmunoassay and expressed as a function of the simultaneous level of plasma osmolality. When the subjects were hydropenic and recumbent, a highly significant correlation between plasma AVP and osmolality was observed that was described by the regression equation y = 0.35 (x -281.0) where y represents the plasma AVP concentration in pg/ml and x the plasma osmolality in mosmol/kg. When these same hydropenic subjects were studied in the upright position, a maneuver that reduces intrathoracic blood volume, plasma AVP and osmolality still showed a significant correlation, but the regression equation describing this relation, y = 0.31 (x -277.8), occupied a position significantly to the left of that found during recumbency. Conversely, when the same subjects were studied during infusion of hypertonic saline, a procedure that increases blood volume, plasma AVP and osmolality again correlated significantly but the regression equation describing this relation, y = 0.32 (x -282), now occupied a position significantly to the right of that obtained during recumbent and hydropenic conditions. These results indicate that moderate increases or decreases in blood volume do influence the osmoregulation of AVP in man, but the effects are relatively small and limited to adjustments in the set of the receptor toward higher or lower levels of osmolality.