OBJECTIVE Effective protection from the risk of variceal bleeding is achieved when the hepatic venous pressure gradient is reduced to 12 mmHg or at least by 20% of baseline values. Such a marked decrease is rarely achieved with propranolol, and new agents or combinations of them are now being explored. The present randomized study investigated whether chronic treatment with the combination of propranolol plus molsidomine, a preferential venous dialator that reduces hepatic venous pressure gradient and does not cause pharmacological tolerance, achieves greater reduction in hepatic venous pressure gradient than propranolol alone. METHODS A hemodynamic study was performed in 34 patients with cirrhosis with portal hypertension in baseline conditions and after 3 months of chronic oral treatment with propranolol alone (n = 19) or propranolol plus molsidomine (n = 15). RESULTS Propranolol produced a significant reduction in hepatic venous pressure gradient (-16%, p < 0.01). Propranolol plus molsidomine also caused a slight but significant decrease in hepatic venous pressure gradient (-9%, p < 0.05). Hepatic blood flow and the hepatic and intrinsic clearance of indocyanine green were significantly reduced by propranolol. The combined administration of propranolol+molsidomine significantly reduced hepatic blood flow but not hepatic and intrinsic clearance of indocyanine green. Both treatment groups produced similar reduction in azygos blood flow, heart rate and cardiac output. However, contrary to propranolol alone, propranolol plus molsidomine did not increase cardiopulmonary pressures. CONCLUSIONS The current study shows that although the combined administration of propranolol plus molsidomine prevents some of the adverse effects of propranolol on liver function and cardiopulmonary pressures, it does not achieve a greater reduction in hepatic venous pressure gradient than propranolol alone and therefore, does not support the use of this combined therapy for the pharmacological treatment of portal hypertension.