The dose requirements and duration of effect of transdermal nitroglycerin in patients with heart failure are not clearly established. In a first series of eight patients with chronic heart failure we gave transdermal nitroglycerin in incremental doses until pulmonary capillary wedge pressure fell at least 30% within 4 hr in three consecutive patients. Thus we found that a single dose of 60 mg/24 hr (120 cm2) was the minimal effective dose. Transdermal nitroglycerin or placebo was then given as a single application of 60 mg/24 hr in random double-blind fashion to 15 additional patients with heart failure (eight received transdermal nitroglycerin and seven received placebo), and hemodynamics were monitored for up to 24 hr. After administration of transdermal nitroglycerin, the control pulmonary capillary wedge pressure of 22 +/- 7 mm Hg fell by 6 +/- 6 mm Hg at 2 hr (p less than .05) and reached maximal reduction of 8 +/- 6 mm Hg (p less than .01) at 4 hr. The reduction in wedge pressure remained significant through 12 hr but was no longer statistically significant by 18 hr after administration of the drug. Transdermal nitroglycerin also significantly reduced pulmonary arterial and right atrial pressures as well as pulmonary vascular resistance from 4 through 12 hr but did not affect systemic hemodynamics. No significant hemodynamic changes occurred after administration of placebo. Thus transdermal nitroglycerin is an effective vasodilator in patients with heart failure, but a dose of at least 60 mg/24 hr is needed. Even with this dose, hemodynamic effects do not last beyond 18 hr, suggesting altered absorption or development of tolerance.