Vasodilators produce beneficial acute hemodynamic effects in patients with congestive heart failure and are employed in long-term management. Tolerance has developed with respect to the hemodynamic effects of prazosin in heart failure, whereas the long-term effects of nitrates are little known. Hemodynamic values were measured in 19 patients with chronic left heart failure before and 90 minutes after oral administration of 40 mg of isosorbide dinitrate. Patients were then randomly assigned in double-blind fashion to receive isosorbide dinitrate (9 patients) or placebo (10 patients), 40 mg four times daily, for 3 months, after which hemodynamic values were measured again before and 90 minutes after administration of the test drug. Both groups of patients responded similarly with a significant decrease in pulmonary wedge and systemic arterial pressures after the first dose of nitrate. After 3 months of isosorbide dinitrate treatment the pulmonary wedge pressure was significantly below control values (-2.5 ± 0.9 mm Hg [mean ± standard error of the mean]; p <0.02) and decreased another 5.4 ± 1.5 mm Hg after a dose of isosorbide dinitrate (p <0.01). In the placebo group, pulmonary wedge pressure at 3 months was unchanged from control values (-1.2 ± 2.1 mm Hg) and failed to change significantly after another dose. In the nitrate-treated group a dose of isosorbide dinitrate at 3 months also reduced mean systemic arterial pressure (-9.3 ± 2.0 mm Hg; p <0.01) and systemic vascular resistance (-7.8 ± 3.7 units; p <0.05). Thus, long-term administration of isosorbide dinitrate is associated with sustained hemodynamic effects and hemodynamic responsiveness in patients with congestive heart failure.