Abnormal hemodynamics play a central role in the development and perpetuation of high blood pressure. We hypothesized that hypertension therapy guided by noninvasive hemodynamics with impedance cardiography could aid primary care physicians in reducing blood pressure more effectively. Uncontrolled hypertensive patients on 1 to 3 medications were randomized by 3:2 ratio to either a standard arm or hemodynamic arm that used impedance cardiography (BioZ, CardioDynamics). Each patient completed 5 study visits with a 2-week washout period followed by 3 months of treatment. A total of 164 patients from 11 centers completed the study, 95 in the standard arm and 69 in the hemodynamic arm. At baseline and after washout, there were no differences between arms in number of medications or demographic, blood pressure, or hemodynamic characteristics. Systolic blood pressure reductions in the hemodynamic arm were greater from baseline (19 mm Hg versus 11 mm Hg; P<0.01) and after washout (25 mm Hg versus 19 mm Hg; P<0.05). Diastolic blood pressure reductions were also greater in the hemodynamic arm from baseline (12 mm Hg versus 5 mm Hg; P<0.001) and after washout (17 mm Hg versus 10 mm Hg; P<0.001). The hemodynamic arm achieved goal blood pressure (<140/90 mm Hg) more frequently (77% versus 57%; P<0.01) and a more aggressive blood pressure level (<130/85 mm Hg) more frequently (55% versus 27%; P<0.0001). These study results indicate that antihypertensive therapy guided by impedance cardiography in uncontrolled hypertensive patients on >/=1 medications is more effective than standard care.