To evaluate the effect of systemically administered atrial natriuretic hormone (ANH) on osmotically induced secretion of arginine vasopressin (AVP) and thirst sensation, 11 healthy men, aged 18 to 28 years, were studied on four occasions. The intravenous infusions of placebo (P) or one of three doses of ser-tyr28 human ANH (0.6 [LD], 1.8 [MD], and 5.4 [HD] pmol/kg/min) were given in random order over 2 hours. During the second hour, subjects also received a 5% saline (HS) infusion (0.1 ml/kg/min). The baseline parameters were similar on each of the study days. Plasma ANH levels increased approximately twofold, eightfold, and 25-fold during LD, MD, and HD infusions, respectively. HS infusion caused increases in serum sodium level (5 to 7 mEq/L) and osmolality (14 to 15 mOsm/L) (p < 0.001). During HS infusion on P day, ANH levels almost doubled (p < 0.001). AVP levels remained stable during the first hour of ANH infusions. An addition of HS caused a significant increase in AVP levels (p < 0.001). The magnitude of this increase was similar on each of the study days. Similarly, thirst perception increased significantly (p < 0.01) and to the same extent during HS infusion on all study days. Both AVP levels and thirst showed a very good correlation with serum osmolality on each of the study days, and there were no significant differences between any of the slopes or intercepts. We conclude that short-term elevation of plasma ANH levels up to 25-fold affects neither the osmotically stimulated secretion of AVP nor thirst perception.