The purpose of our study was to determine the effects of treatment with hydrochlorothiazide (n = 10) or diltiazem (n = 8) on reflex humoral, hemodynamic, and vascular responses to graded lower body negative pressure in subjects with mild to moderate hypertension (supine diastolic pressure, 95–114 mm Hg). All subjects received placebo for 2 to 4 weeks followed by either hydrochlorothiazide (25–50 mg b.i.d.) or diltiazem (120–180 mg b.i.d.) to achieve a reduction in supine diastolic pressure of 10 mm Hg or more and a final pressure below 90 mm Hg. Mean arterial pressure, forearm vascular resistance, plasma norepinephrine, and renin responses to graded lower body negative pressure (−10, − 20, − 40 mm Hg) and head-up tilt were examined before and after 12 weeks of treatment with either drug. Pretreatment basal values of mean arterial pressure (114 ± 2 vs 117 ± 2 mm Hg), forearm vascular resistance (29 ± 3 vs 35 ± 7 units), and plasma renin activity (0.7 ± 0.2 vs 0.6 ± 0.2 ng angiotensin I/ml/hr) were not significantly different between groups. There were no significant differences in basal plasma norepinephrine or in the increases of norepinephrine in response to lower body negative pressure before and after treatment in either group. Forearm vascular resistance responses to lower body negative pressure were virtually abolished in the diltiazem-treated group but not in the hydrochlorothiazide-treated group despite similar levels of mean arterial pressure and basal forearm vascular resistance. Plasma renin activity was significantly higher in the hydrochlorothiazide-treated group after therapy, but the change in renin activity in response to lower body negative pressure was similar before and after therapy in either group. These results suggest that the reflex neurogenic vasoconstriction during lower body negative pressure is inhibited by diltiazem through deactivation of calcium-dependent contractile responses of vascular smooth muscle in the forearm.