Arterial oxygen desaturation is commonly found in patients with cirrhosis of the liver, but severe hypoxemia is unusual. To investigate the mechanism of the impairment in gas exchange, six severely hypoxemic (mean PaO2, 55.9 +/- 5.9 mm Hg) cirrhotic patients (five confirmed by biopsy), without pulmonary or cardiovascular disease and in the absence of acute hepatic disease, were submitted to right heart catheterization. Inequalities of VA/Q were estimated in the respiratory steady state using the multiple inert gas technique. The mean pulmonary arterial pressure was low (7.2 +/- 2.3 mm Hg) and the cardiac output high (Q = 11.0 +/- 2.06 L/min), indicating a low PVR. The VA/Q mismatching of the ventilated and perfused units ranged from mild to moderate, but a large percentage of Q flowed through unventilated areas. Furthermore, there was a significant difference between predicted and measured PaO2 (9.27 +/- 5.9 mm Hg; p less than 0.01), which was attributed to either an unmeasured postpulmonary shunt (between portal and pulmonary vein) or a diffusion defect. The impairment in gas exchange in these patients is thus due primarily to an intrapulmonary, and possibly extrapulmonary, shunt. This was thought to be due mainly to an impaired regulatory mechanism of the microcirculation by the hepatic dysfunction.