Exercise duration and maximal oxygen uptake in patients with heart failure are not suddenly increased after the administration of hemodynamically effective doses of a vasodilator, but they are increased after long-term treatment with these drugs. To explore these differing responses, we had 16 patients with chronic left ventricular failure perform exercise to symptomatic maximum before and 90 minutes after the oral administration of a single 40 mg dose of isosorbide dinitrate. Exercise was then repeated after three months of randomly assigned double-blind long-term treatment with isosorbide dinitrate (eight patients) or placebo (eight patients). Maximal oxygen consumption at control averaged 12.9 ± 1.8 ml/kg/min in the group subsequently assigned to isosorbide dinitrate, and 13.9 ± 1.7 ml/kg/min in the group given the placebo. After the first dose of nitrate, maximal oxygen consumption was unchanged in either group. After three months of nitrate treatment, maximal oxygen consumption increased by 58 percent to 19.4 ± 3.1 ml/kg/min (p < 0.02) whereas in the group receiving the placebo it was unchanged at 13.3 ± 1.5 ml/kg/min. After the first dose of isosorbide dinitrate resting pulmonary wedge pressure was lowered similarly by 7.5 ± 1.1 and 9.6 ± 1.0 mm Hg in the two groups (both p < 0.001). At three months the patients receiving nitrate, but not the patients receiving the placebo, exhibited a reduced pulmonary wedge pressure at rest. Maximal exercise hemodynamics were not significantly changed in either group at three months. The arteriovenous oxygen difference at peak exercise was increased by 3.2 ± 0.9 vol percent after three months of nitrate treatment (p < 0.01) but was unchanged by placebo. Thus, exercise capacity is not improved after a hemodynamically effective first dose of isosorbide dinitrate, but exercise tolerance is improved long-term in the same patients with heart failure. This improvement may be related to peripheral factors rather than a change in cardiac performance during exercise.