Abstract-Ghrelin is a growth hormone-releasing peptide secreted by the stomach with potent effects on appetite.Experimental and clinical studies indicate that ghrelin also influences cardiovascular regulation and metabolic function and mediates behavioral responses to stress. We investigated the effects of ghrelin on blood pressure (BP), sympathetic nervous system activity, and mental stress responses in lean (nϭ13) and overweight or obese (nϭ13) individuals. Subjects received an intravenous infusion of human ghrelin (5 pmol/kg per minute for 1 hour) and saline in a randomized fashion. Ghrelin decreased systolic (Ϫ6 and Ϫ11 mm Hg) and diastolic BP (Ϫ8 mm Hg for both), increased muscle sympathetic nervous system activity (18Ϯ2 to 28Ϯ3 bursts per min, PϽ0.05 and from 21Ϯ2 to 32Ϯ3 bursts per min, PϽ0.001) in lean and overweight or obese subjects, respectively, without a significant change in heart rate, calf blood flow, or vascular resistance. Ghrelin induced a rise in plasma glucose concentration in lean individuals (PϽ0.05) and increased cortisol levels in both groups (PϽ0.05). Stress induced a significant change in mean BP (ϩ22 and ϩ27 mm Hg), heart rate (ϩ36 and ϩ29 bpm), and muscle sympathetic nervous system activity (ϩ6.1Ϯ1.6 and ϩ6.8Ϯ2.7 bursts per min) during saline infusion in lean and overweight or obese subjects, respectively. During ghrelin infusion, the changes in BP and muscle sympathetic nerve activity in response to stress were significantly reduced in both groups (PϽ0.05). In conclusion, ghrelin exerts unique effects in that it reduces BP and increases muscle sympathetic nervous system activity and blunts cardiovascular responses to mental stress. These responses may represent a combination of peripheral (baroreflex-mediated) and central effects of ghrelin. (Hypertension. 2011;58:43-50.)