The hemodynamic responses to acute vasodilator administration were evaluated in 163 patients who were entered into the National Institutes of Health Registry on Primary Pulmonary Hypertension (PPH) between 1981 and 1985. Of a total of 491 drug administrations in these patients, 135 administrations in 104 patients were performed in a manner acceptable to the Registry. A single vasodilator was tried in 79 patients and more than one vasodilator in 25 patients. Two-thirds of the patients were in New York Heart Association Functional Classes III or IV. When the effects of all vasodilators were grouped together, there were significant decreases from baseline in mean pulmonary artery pressure (60 ± 2 to 57 ± 2 mm Hg, p < 0.05) and total pulmonary resistance index (32.5 ± 1.7 to 25.1 ± 1.4 mm Hg/L/min/m2, p < 0.0001), and increases in cardiac index (2.1 ± 0.1 to 2.7 ± 0.1 L/min/m2, p < 0.0001). Mean systemic blood pressure fell (88 ± 1 to 79 ± 1 mm Hg, p < 0.0001), whereas Pa(O2) was unchanged (70 ± 3 to 71 ± 3 mm Hg, p = NS). A fall in total pulmonary resistance greater than 20% was observed in 55% of the adequate drug trials. Adverse effects occurred in 32 of the total 491 patient-drug trials and were generally minor. Hypotension requiring treatment developed in six patients. There were two deaths attributable to vasodilator administration. Patients who died or had hypotension requiring treatment had higher right atrial pressures than did other treated patients (15 ± 2 versus 9 ± 1 mm Hg, p < 0.05). These data suggest that acute vasodilator administration in a substantial proportion of PPH patients can produce at least a modest reduction in total pulmonary resistance.