1. The acute administration of milrinone, a positive inotropic vasodilator agent, improves resting hemodynamic function and maximal and submaximal metabolic responses to exercise in patients with severe congestive heart failure. 2. To determine whether the improvement in exercise capacity induced by milrinone administration can be predicted by its acute positive inotropic and/or vasodilator effects at rest, milrinone was administered intravenously (progressive doses of 12.5 to 75 microns/kg) to 15 patients with heart failure (functional classes III and IV, New York Heart Association) at rest, and during maximal upright exercise testing on a cycle ergometer. Serum drug levels were matched for the resting and exercise tests. Drug administration for exercise tests was placebo-controlled and double-blind. 3. At rest, milrinone administration caused substantial decreases in right atrial pressure (-53%), left ventricular end-diastolic pressure (-30%), and systemic vascular resistance (-35%); and increases in cardiac index (+59%), peak positive dP/dt (+20%) and stroke work index (+51%). Administration of milrinone during exercise resulted in a 15% increase in peak oxygen uptake and a 16% increase in anaerobic threshold. However, none of the changes in resting hemodynamic function correlated significantly in magnitude with the changes in peak oxygen uptake and anaerobic threshold. 4. Thus, the acute improvement in exercise capacity that occurs with milrinone is not predicted by the positive inotropic or vasodilator effects of the drug at rest.