The effects of 75 ml ethanol ingested over 60 min on plasma osmolality (Posmol) and plasma vasopressin (PAVP) in four normal subjects were studied. In the 1st h of the investigation PAVP fell, then rose, even though plasma ethanol levels were still rising. The rise in PAVP was preceded by a rise in Posmol corrected for the influence of ethanol. The fall in PAVP was followed by an increase in free water clearance and a decrease in urine osmolality, while the later rise in PAVP was followed by a decrease in free water clearance (CH2O) and a rise in urine osmolality. The relationship between PAVP and Posmol was then studied during intravenous (iv) hypertonic saline infusion in five subjects. The results were compared with those from a second infusion in the same subjects after ingestion of ethanol (0.5 ml/kg). Ethanol reduced vasopressin release in response to iv hypertonic saline infusion, and this correlated with a reduced decrease in CH2O. We conclude that ethanol inhibits PAVP release by decreasing the response of the osmosodium receptors to changes in plasma tonicity.