This study was designed to investigate whether the addition of nitroglycerin to vasopressin infusion could avoid the deleterious systemic effects of vasopressin while maintaining or enhancing the therapeutic benefits of portal pressure reduction. The effect of nitroglycerin on splanchnic and systemic hemodynamics was studied in cirrhotic patients and portal hypertensive dogs receiving i.v. vasopressin. During i.v. vasopressin infusion (0.4 units per min), the cardiac output decreased in patients by 14% from 7.6 ± 0.9 (mean ± S.E.) to 6.5 ± 0.7 liters per min, p < 0.01, the mean arterial pressure increased 21% from 87 ± 2 to 105 ± 4, p < 0.01, and the heart rate decreased 11% from 79 ± 3 to 71 ± 3, p < 0.01. The administration of sublingual nitroglycerin (0.4 mg) returned all the systemic hemodynamic parameters to baseline values. In dogs, vasopressin infusion significantly reduced portal pressure and flow while increasing portal venous resistance. Nitroglycerin when added to the vasopressin infusion reduced portal venous resistance and further decreased portal pressure in dogs. In patients, vasopressin reduced the hepatic blood flow (44%), wedged hepatic venous pressure (11%), and the gradient between wedged and free hepatic venous pressures (23%). Nitroglycerin administration caused a further reduction of the wedged hepatic venous pressure (23.6 ± 2.3 to 21.1 ± 2.0, 11%, p < 0.01). There was a small but not significant further decline (7%) in the hepatic venous pressure gradient. These results provide evidence that the addition of nitroglycerin to an i.v. infusion of vasopressin reversed the detrimental effects of vasopressin while preserving the beneficial effects.