Ro 15–1788, a benzodiazepine antagonist, has been advocated as a new treatment for hepatic encephalopathy. This drug is extensively metabolized by the liver in normal subjects. In the present study, we examined Ro 15–1788 disposition in eight healthy controls (Group I), eight cirrhotic patients with moderately impaired liver function (Pugh score >10, Group II) and eight patients with severe liver dysfunction (Pugh score > 10, Group III). The subjects of each group were age and sex matched. After an intravenous infusion of 2 mg Ro 15–1788 over 5 ḿin, blood samples were taken at fixed intervals up to 7 hr after the infusion. Plasma levels of the drug were determined by capillary gas chromatography. In controls, Ro 15–1788 had a high plasma clearance [16.3 ± 2.6 ml per min per kg (mean ± S.D.)], a short half-life (45.7 ± 8.5 min), a large volume of distribution (0.62 ± 0.09 liter per kg) and a low plasma protein binding (45 ± 6%). Plasma clearance was reduced markedly in both groups of cirrhotic patients (-57 and −74%, respectively); the volume of distribution was unchanged in Group II and moderately increased in Group III (+37%). The elimination half-life was markedly prolonged in Groups II and III (+66 and +210%, respectively). Plasma clearance and Pugh score were highly correlated in cirrhotic patients (r = 0.830, p < 0.001). The plasma protein binding of Ro 15–1788 was lower in cirrhotics, resulting in a significant increase in the free fraction of the drug (+16% in Group II; +44% in Group III). These findings emphasize the need for adjustment of Ro 15–1788 dosage in cirrhotic patients, particularly in those with severe liver failure.