Intranasal administration of angiotensin II (ANGII) affects blood pressure in a mode different from intravenously administered ANGII via a direct access to the brain bypassing the blood-brain barrier. This clinical study investigated blood pressure regulation after intranasal ANGII administration in healthy humans, whereas systemic, blood-mediated effects of ANGII were specifically blocked. In a balanced crossover design, men (n=8) and women (n=8) were intranasally administered ANGII (400 μg) or placebo after ANGII type 1 receptors had been blocked by pretreatment with valsartan (80 mg; 12 and 6 hours before intranasal administration). Plasma levels of ANGII, aldosterone, renin, vasopressin, and norepinephrine were measured; blood pressure and heart rate were recorded continuously. Intranasal ANGII acutely decreased blood pressure without altering the heart rate. Plasma levels of vasopressin and norepinephrine remained unaffected. Plasma ANGII levels were increased throughout the recording period. Aldosterone levels increased despite the peripheral ANGII type 1 receptor blockade, indicating an aldosterone escape phenomenon. In conclusion, intranasal ANGII reduces blood pressure in the presence of selective ANGII type 1 receptor blockade. Intranasal ANGII administration represents a useful approach for unraveling the role of this peptide in blood pressure regulation in humans.