To assess the potential beneficial effects of a nonparenteral vasodilator, sublingual isosorbide dinitrate (5 to 15 mg.) was administered in 12 patients with chronic congestive heart failure refractory to conventional therapy. Hemodynamic measurements were performed before and at 15 minute intervals after drug administration for 90 minutes. Venous capacitance was measured at 5 minute intervals. Myocardial metabolism was also studied in five patients before and after drug administration. Hemodynamic effects were characterized by a modest decrease in mean arterial pressure (85 +/- 3 to 78 +/- 2 [S.E.M.] mm. Hg) and substantial decrease in right atrial (10 +/- 1 to 6 +/- 1), pulmonary arterial (39 +/- 4 to 30 +/- 4) and pulmonary capillary wedge pressures (28 +/- 2 to 21 +h- 2). These changes were accompanied by an increase in venous capacitance (2.46 +/- 0.16 to 3.99 +/- 0.24 c.c./100 c.c. of tissue). Along with a decrease in left ventricular filling pressure, cardiac index increased (1.99 +/- 0.13 to 2.37 +/- 0.15 L./min/M.2). No significant effect on heart rate was seen. Delta P/delta t, an index related to left ventricular dp/dt, increased in all but one patient (253 +/- 31 to 298 +/- 39 mm. Hg/sec.) (p less than 0.02 for all changes) in the face of decreased preload and afterload and unchanged heart rate, suggesting improved contractile state. A decrease in coronary blood flow (165 +/- 13 to 131 +/- 15 c.c./min.) and myocardial oxygen consumption (18.1 +/- 1.6 to 14.5 +/- 1.6 c.c./min.) was noted (p less than 0.02). No change in arterial-coronary sinus oxygen difference or lactate extraction was observed. These data demonstrate that the objectives of therapy in congestive heart failure, namely improved forward output and decreased ventricular filling pressures, can be achieved without metabolic deterioration by using sublingual isosorbide. The mechanisms responsible are related to diminished impedence to ventricular ejection and peripheral pooling of blood. Since the duration of action does not usually exceed 90 minutes, frequent drug administration may be a source of patient inconvience.