The efficacy of orally administered isosorbide dinitrate (IS) has been questioned. Recently, vasodilators have been shown to lower left ventricular filling pressure (LVFP) and raise cardiac output in heart failure. In this study, oral IS was evaluated in 12 patients with high LVFP due to heart failure. After right heart catheterization, patients with LVFP > 14 mm Hg were randomized double blind to receive either 20 mg IS or placebo (P). Supine heart rate (HR), arterial pressure (BP), and LVFP were monitored for 5 hr. After this, the alternate drug (P or IS) was given, followed by 5 more hr of monitoring. In the 12 patients after receiving IS, LVFP reached a peak reduction of 6.7 mm Hg (-26%, P < 0.005) at 30 min. Significant reduction persisted for 4.5 hr. Blood pressure fell concomitantly with the LVFP. At 60 min HR was unchanged, systolic BP was reduced by 8.9 mm Hg (P < 0.025)and diastolic BP by 6.3 mm Hg (P < 0.005). In the 10 patients receiving P, control values were not significantly different from those given IS, and after receiving P, HR, BP, and LVFP failed to change significantly over the next 5 hr. Thus, oral IS produces a sustained reduction in LVFP and therefore merits further evaluation as chronic therapy for left ventricular failure.