To investigate the mechanisms underlying abnormal gas exchange in liver cirrhosis, 15 patients were studied while breathing room air, 11% O2, and 100% O2 in random sequence. Under basal conditions, patients showed mild reductions from normal in systemic and pulmonary vascular resistance, normal PaO2 (mean, 92.5 .+-. 2.5 mm Hg), mild hypocapnia (mean, 34 .+-. 0.7 mm Hg), and a slightly right-shifted oxyhemoglobin dissociation curve (P50, 27.2 .+-. 0.4 mm Hg; 2,3-DPG, 13.1 .+-. 0.6 .mu.mol/g). Using the multiple inert gas elimination technique, we found mild to moderate ventilation-perfusion (.ovrhdot.VA/.ovrhdot.Q) inequality with a mean of 5% (range, 0 to 20%) of cardiac output (.ovrhdot.QT) perfusing low .ovrhdot.VA/.ovrhdot.Q ratio (< 0.1) areas but no shunt. Breathing 11% O2, there were significant increases in .ovrhdot.Q-, pulmonary artery pressure, and vascular resistance, whereas no changes occurred in .ovrhdot.VA/.ovrhdot.Q distribution, and there was no evidence for alveolar-endcapillary diffusion limitation for O2. In contrast, after 100% O2 shunt developed and .ovrhdot.VA/.ovrhdot.Q relationships worsened without significant hemodynamic changes. Furthermore, patients with cutaneous spider nevi (n = 8) showed more hepatocellular dysfunction (lower prothrombin values), lower systemic and pulmonary vascular resistance, less hypoxic pulmonary vasoconstriction (HPV), lower PaO2, and more .ovrhdot.VA/.ovrhdot.Q mismatch than did those without spiders. Our results confirm, therefore, that HPV is not fully abolished, as previously described, in hepatic cirrhosis. However, those patietns with more advanced hepatic disease exhibit inadequate pulmonary vascular tone, which increases .ovrhdot.VA/.ovrhdot.Q inequality and lowers PaO2.