Present investigations support major contributions from increases in both portal blood flow and portal vascular resistance in the mechanism that maintains portal hypertension. β-Adrenergic blockers have been shown to reduce the elevated portal blood flow component. The possibility that nitroglycerin administration could reduce the elevated portal vascular resistance component is investigated here. Portal hypertension was induced in rats by a calibrated constriction of the portal vein. Portal hypertensive rats receiving placebo exhibited significant (p < 0.05) elevations over normal rats receiving placebo in cardiac index, portal venous inflow and portal pressure. Portal hypertensive rats were then divided into groups receiving nitroglycerin infusion, propranolol (β-adrenergic blockade) and combined administration of nitroglycerin and propranolol. Significant reductions (p < 0.05) in portal blood flow of 30, 32 and 44%, respectively, were accompanied by significant portal pressure reductions of 2.7 ± 0.2, 1.7 ± 0.3 and 3.6 ± 0.4 mm Hg in all groups, respectively (p < 0.05). Nitroglycerin failed to prevent a 46% rise in portal-collateral resistance accompanying the portal blood flow reduction, similar to resistance rises also found in propranolol-treated (33%) and combination nitroglycerin-propranolol-treated (49%) groups. We conclude that nitroglycerin infusion can significantly reduce portal pressure, alone or in combination with β-blockade, by reducing portal venous inflow. It appears that nitroglycerin reduces portal blood flow through the effect of baroreceptor sympathetic reflexes that constrict the splanchnic bed in response to vasodilatation and venous pooling.