Biliary cirrhosis in the rat triggers intrapulmonary vasodilatation and gas exchange abnormalities that characterize the hepatopulmonary syndrome (HPS). This vasodilatation correlates with increased levels of pulmonary microcirculatory endothelial nitric oxide synthase (eNOS) and hepatic and plasma endothelin-1 (ET-1). Importantly, during cirrhosis the pulmonary vascular responses to acute hypoxia are blunted. The purpose of this work was to examine the pulmonary vascular responses and adaptations to the combination of liver cirrhosis and chronic hypoxia. In addition to hemodynamic measurements, we investigated whether pulmonary expression changes of eNOS, ET-1 and its receptor (endothelin A and B), or heme oxygenase 1 (HO-1) in experimental cirrhosis affect the development of hypoxic pulmonary hypertension. We induced cirrhosis in male Sprague-Dawley rats using common bile duct ligation (CBDL) and exposed them to CH (PiO₂ 76 mmHg) or maintained them in Denver (Den, PiO₂ 122 mmHg) for 3 weeks. Our data show: 1) CBDL-CH rats had a persistent blunted hypoxic pulmonary vasoconstriction similar to CBDL-Den; 2) the development of hypoxic pulmonary hypertension was completely prevented in the CBDL-CH rats, as indicated by normal pulmonary artery pressure and lack of right ventricular hypertrophy and pulmonary arteriole remodeling; and 3) a selective increase expression of ET-1, pulmonary ET_B receptor, eNOS and HO-1, are potential mechanisms of protection against hypoxic pulmonary hypertension in the CBDL-CH rats. These data demonstrate that unique and undefined hepatic-pulmonary interactions occur during liver cirrhosis and chronic hypoxia. Understanding these interactions may provide important information for the prevention and treatment of pulmonary hypertension.