Phenylpropanolamine (PPA) overdose can cause severe hypertension, intracerebral hemorrhage, and death. We studied the efficacy and safety of propranolol in the treatment of PPA-induced hypertension. Subjects received propranolol either by mouth for 48 hours before PPA or as a rapid intravenous infusion after PPA. PPA, 75 mg alone, increased blood pressure (31 ± 14 mm Hg systolic, 20 ± 5 mm Hg diastolic), and propranolol pretreatment antagonized this increase (12 ± 10 mm Hg systolic, 10 ± 7 mm Hg diastolic). Intravenous propranolol after PPA also decreased blood pressure. Left ventricular function (assessed by echocardiography) showed that PPA increased the stroke volume 30% (from 62.5 ± 20.9 to 80.8 ± 22.4 ml), the ejection fraction 9% (from 64% ± 10% to 70% ± 7%), and cardiac output 14% (from 3.6 ± 0.6 to 4.1 ± 1.0 L/min). Intravenous propranolol reversed these effects. Systemic vascular resistance was increased by PPA 28% (from 1710 ± 200 to 2190 ± 700 dyne · sec/cm5) and was further increased by propranolol 22% (to 2660 ± 1200 dyne · sec/cm5). We conclude that PPA increases blood pressure by increasing systemic vascular resistance and cardiac output, and that propranolol antagonizes this increase by reversing the effect of PPA on cardiac output. That propranolol antagonizes the pressor effect of PPA is in contrast to the interaction in which propranolol enhances the pressor effect of norepinephrine. This is probably because PPA has less β2 activity than does norepinephrine.