The cardiocirculatory actions of prazosin (PZN) orally were evaluated by cardiac catheterization, forearm plethysmography, echocardiography, treadmill exercise, and symptoms in patients with advanced long-standing congestive heart failure (CHF). PZN orally (2 to 7 mg) reduced forearm venous tone and decreased forearm vascular resistance. Concomitantly mean systemic arterial pressure declined, left ventricular filling pressure (LVFP) decreased, and cardiac index (CI) was raised. These effects of a single dose of PZN on LV function were rapid in onset, maximal at 1 hour, and sustained for the entire 6 hours of observation. After 2 weeks of outpatient therapy with 2 to 7 mg PZN four times daily, echographic LV end-diastolic dimension decreased and the duration of treadmill exercise increased. Symptoms (dyspnea, fatigue, angina) were diminished throughout the course of PZN therapy, and New York Heart Association functional class improved for III to II. Thus PZN possesses sustained nitroprusside-like balanced dilator actions on the systemic arterial and venous beds, which are effectively translated into beneficial hemodynamics of augmenting lowered cardiac output and relieving excessive LVFP. Delayed vasodilator tolerance, occurring in 30% of patients, is prevented by prior use of aldosterone antagonists and is easily treated. Subacute hemodynamic suppression of beneficial PZN vasodilator actions is transient and does not preclude successful sustained PZN therapy of severe chronic CHF.