This study investigated whether oral doses of isosorbide-5-mononitrate, a preferential venous dilator that decreases portal pressure, could enhance the effects of propranolol on portal hypertension. Taking part in the stuty were 28 patients with cirrhosis and portal hypertension. Twenty patients (group 1) had hemodynamic measurements in baseline conditions after beta-blockade by intravenous administration of propranolol and after receiveing oral doses of isosorbide-5-mononitrate. The remaining eight patients (group 2) were given oral isosorbide-5-mononitrate while receiving chronic propranolol therapy. In group 1, propranolol significantly reduced portal pressure (estimated as the gradient between wedged and free hepatic venous pressures) from 21.5 ± 3.9 to 18.6 ± mm Hg (-13.7%, p <0.001), azygos blood flow (-38%, p < 0.001), hepatic blood flow (−12.8%, p < 0.05), cardiac output (−24.5%, p < 0.001) and heart rate (−18.4%, p < 0.001) without significant changes in mean arterial pressure. Addition of oral isosorbide-5-mononitrate caused a further and marked fall in portal pressure (to 15.7 ± 3.1 mm Hg, p < 0.001), without additional changes in azygos blood flow but with significant additional reductions in hepatic blood flow (−15.5%, p < 0.05), cardiac out put (−11.5%, p < 0.001) and mean arterial pressure (−22%, p < 0.001). The additional effect of isosorbide-5-mononitrate on portal pressure was especially evident in patients who did not respond to propranolol (decrease in portal pressure less than 10%, n = 9), the final reduction in portal pressure after combined therapy being similar in propranolol responders (−26%) and nonresponders (−27%). In group 2, the association of isosorbide-5-mononitrate to chronic propranolol therapy also caused a further significant reduction in portal pressure, from 17.1 ± 3.1 to 15.4 ± 2.1 mm Hg (p < 0.05). Study results indicate that isosorbide-5-mononitrate enhances the beneficial effects of propranolol on portal hypertension in patients with cirrhosis.