AimIn cirrhosis, increased oxidative stress leads to systemic and splanchnic hyperdynamic circulation, splanchnic angiogenesis, portosystemic collaterals formation, hepatic endothelial dysfunction, increased intrahepatic resistance, and the subsequent portal hypertension. Like N-acetylcysteine, hydrogen-rich saline is a new documented antioxidant with the potential to treat the complications of liver diseases.Methods In this study, hemodynamics, splanchnic angiogenesis, and hepatic endothelial dysfunction were measured in common bile duct ligation (BDL)-cirrhotic rats that receiving one-month treatment of vehicle, N-acetylcysteine and hydrogen-rich saline immediately after BDL. Additionally, acute effects of N-acetylcysteine and hydrogen-rich saline on vascular endothelial growth factor (VEGF)-induced tubule formation and migration of human umbilical vein endothelial cells (HUVECs) were also evaluated.ResultsThe data indicate that one-month treatment of N-acetylcysteine or hydrogen-rich saline significantly ameliorated systemic and splanchnic hyperdynamic circulation, corrected hepatic endothelial dysfunction, and decreased intrahepatic resistance and mesenteric angiogenesis by inhibiting inflammatory cytokines, nitric oxide, VEGF and reducing mesenteric oxidative stress in cirrhosis rats. In vivo studies revealed that acute co-incubation of N-acetylcysteine or hydrogen-rich saline with VEGF effectively suppressed VEGF-induced angiogenesis and migration of HUVECs that accompanied by decreasing of oxidative stress and inflammatory cytokines.Conclusions Both hydrogen-rich saline and N-acetylcysteine alleviate portal hypertension, the severity of portosystemic collaterals, mesenteric angiogenesis, hepatic endothelial dysfunction, and intrahepatic resistance in cirrhotic rats. N-acetylcysteine and the new antioxidant, hydrogen-rich saline are potential treatments for the complications of cirrhosis.