Although a vasodilator drug might favorably alter hemodynamics in resting, supine patients with heart failure, it must be determined if the drug has any unfavorable as well as favorable effects under extremes of real life stress situations normally encountered by ambulatory patients, especially upright exercise. An adverse response might occur with the addition of pharmacologic vasodilation to the metabolic arteriolar dilation accompanying upright exercise. In order to evaluate these factors in a controlled environment, 7 NYHA class 2-3 patients with congestive heart failure without angina pectoris or stenotic valvular lesions performed upright bicycle exercise pre- and postadministration of a maximally-tolerated dose of 2% nitroglycerin ointment, determined previously by titration. Nitroglycerin therapy resulted in slightly improved cardiac performance at two given submaximal workloads. Also noted was, at a higher workload, a decreased ratio of arteriovenous oxygen difference to cardiac index suggestive of increased circulatory reserve. Pulmonary capillary wedge pressure, total body oxygen consumption, plasma catecholamines, and blood lactates did not show a statistically significant change after use of nitroglycerin ointment, nor were symptoms of fatigue or dyspnea improved during exercise. It is concluded that nitroglycerin ointment does not remarkably improve hemodynamics or alter nutritional blood flow to exercising muscle at a submaximal upright upright workload. From our data and that of others, it is concluded that nitroglycerin ointment can be given safely to heart failure patients to improve resting supine hemodynamics without adversely affecting upright exercise performance or hemodynamics.