Background: Major depressive disorder (MDD) is associated with sympathetic overactivity and alterations in peripheral adrenergic receptor function; however, no studies have directly assessed vasoconstrictor responsiveness in adults with MDD. We tested the hypotheses that β-adrenergic receptor-mediated vasodilation would be blunted in adults with MDD compared with healthy nondepressed adults (HA) and would functionally contribute to exaggerated norepinephrine-induced vasoconstriction. Methods: In 13 HA (8 female; 24±4 years) and in 12 adults with MDD (8 female; 22±3 yrs), red blood cell flux was measured during graded intradermal microdialysis perfusion of the β-adrenergic receptor agonist isoproterenol (10 ⁻¹⁰ to 10 ^{− 4} mol/L) and, separately, during the perfusion of norepinephrine (10 ^{− 12} to 10 ^{− 2} mol/L), alone and in combination with the β-adrenergic receptor antagonist propranolol (2 mmol/L). Nonadrenergic vasoconstriction was assessed via perfusion of angiotensin II (10 ^{− 12} to 10 ^{− 4} mol/L). Results: Isoproterenol-induced vasodilation was blunted in adults with MDD (188.9±70.1 HA versus 128.3±39.4 au MDD, P =0.025). Net norepinephrine-induced vasoconstriction was exaggerated in adults with MDD (−0.16±0.54 HA versus -0.75±0.56 au MDD, P =0.014); however, there were no group differences in angiotensin II–induced vasoconstriction. Propranolol potentiated norepinephrine-induced vasoconstriction in HA (−0.16±0.54 norepinephrine versus −1.60±1.40 au propranolol, P <0.01) but had no effect in adults with MDD (−0.75±0.56 norepinephrine versus −1.58±1.56 au propranolol, P =0.08). Conclusions: β-adrenergic receptor-mediated microvascular vasodilation was blunted in adults with MDD and contributed to exaggerated adrenergic vasoconstriction. The relative loss of the vasoprotective effect of β-adrenergic receptor-mediated vasodilation may contribute to increased peripheral resistance, thereby driving the development of hypertension in adults with MDD.